N-[(4-Heteroaryl-1-Piperidinyl)Alkly] Phthalimides and related compounds and their therapeutic utility

ABSTRACT

Heteroarylpiperidines, pyrrolidines, and piperazines are useful as antipsychotic and analgesic agents. The compounds are especially useful for treating psychoses by administering to a mammal a psychoses-treating effective amount of one of the compounds. Depot derivatives of the compounds are useful for providing long acting effects of the compounds. The compounds are also useful as analgesics by administering a pain-relieving effective amount of one of the compounds to a mammal.

This is a division of pending application Ser. No. 08/329,000 filed Oct.25, 1994 U.S. Pat. No. 5,776,963 of Joseph T. Strupczewski, Grover C.Helsley, Edward J. Glamkowski, Yulin Chiang, Kenneth J. Bordeau, PeterA. Nemoto and John J.Tegaler for HETEROARYLPIPERIDINES, PYRROLIDINES ANDPIPERAZINES AND THEIR USE AS ANTIPSYCHOTICS AND ANALGETICS, which is aCIP application of Ser. No. 08/144,265, filed Oct. 28, 1993, abandoned,which is a CIP application of Ser. No. 07/969,383, filed Oct. 30, 1992,U.S. Pat. No. 5,364,866 which is a CIP application of Ser. No.07/788,269, filed Nov. 5, 1991, now abandoned, which is a CIPapplication of Ser. No. 07/944,705, filed Sep. 5, 1991, now abandoned,which is a continuation application of Ser. No. 07/619,825, filed Nov.29, 1990, now abandoned, which is a continuation application of Ser. No.07/456,790, filed Dec. 29, 1989, now abandoned, which is a CIPapplication of Ser. No. 07/354,411, filed May 19, 1989, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to heteroarylpiperidines, pyrrolidines andpiperazines. More particularly, this invention relates toheteroarylpiperidines, pyrrolidines and piperazines having antipsychoticactivity and to their use as antipsychotic drugs.

The therapeutic treatment of schizophrenic patients by administration ofneuroleptic drugs, such as chlorpromazine, haloperidol, sulpiride, andchemically closely related compounds, is widespread. While control ofschizophrenic symptoms has been successful, treatment with these drugsdoes not cure the psychotic patient, who will almost certainly relapseif medication is discontinued. There exists a continuing need in the artfor antipsychotic drugs for the treatment of psychoses.

Moreover, some of the known neuroleptics produce unwanted side effects.For example, the side effects of many antipsychotic drugs include theso-called extrapyramidal symptoms, such as rigidity and tremor,continuous restless walking, and tardive dyskinesia which causes facialgrimacing, and involuntary movements of the face and extremities.Orthostatic hypotension is also common. Thus, there also exists a needin the art for antipsychotic drugs that produce fewer or less severemanifestations of these common side effects.

In addition, because of the frequent long term administration ofneuroleptics and the problems with patient compliance, there is afurther need in the art for long lasting neuroleptics, which can beformulated into sustained release depot preparations, without the sideeffects previously mentioned.

Moreover, there has been a need for drugs that can produce otherbiological effects. For example, relief from pain has been an age-oldaspiration which has led to the discovery of natural and syntheticanalgetics. Nevertheless, the need for safe and effective analgetics hascontinued to the present day.

SUMMARY OF THE INVENTION

This invention aids in fulfilling these needs in the art by providing acompound of the formula: ##STR1## wherein X is --O--, --S--, --NH--, or--N(R₂)--

R₂ is selected from the group consisting of lower alkyl, aryl loweralkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl andphenylsulfonyl groups;

p is 1 or 2;

Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine,iodine, lower alkoxy, trifluoromethyl, nitro, or amino;

Q₁ is selected from the group consisting of: ##STR2## where Z is##STR3## and Y₂ is selected from the group consisting of: ##STR4## inwhich (R₁) is --CR₂₄ R₂₇ --(CR₂₃ R₂₄)_(n) --CR₂₄ R₂₇ -- where n is0,1,2, or 3; or

--CHR₂₄ --CH═CH--CHR₂₄ --,

--CHR₂₄ --C.tbd.C--CHR₂₄ --,

--CHR₂₄ --CH═CH--CR₂₃ R₂₄ --CHR₂₄ --,

--CHR₂₄ --CR₂₃ R₂₄ --CH═CH--CHR₂₄ --,

--CHR₂₄ --C.tbd.C--CR₂₃ R₂₄ --CHR₂₄ --, or

--CHR₂₄ --CR₂₃ R₂₄ --C.tbd.C--CHR₂₄ --,

the CH═CH-- bond being cis or trans;

R and m are as defined hereinafter;

R₂₃ is hydrogen, alkyl, aryl, hydroxy, alkoxy, aryloxy, arylalkyloxy,alkanoyloxy, hydroxy lower alkyl, alkoxy lower alkyl, aryloxy loweralkyl, arylalkyl oxy lower alkyl, alkanoyloxy lower alkyl or ##STR5##where Z₁ is lower alkyl, --OH, lower alkoxy, --CF₃, --NO₂, --NH₂ orhalogen; and

R₂₄ is hydrogen, alkyl, aryl, hydroxy lower alkyl, alkoxy lower alkyl,aryloxy lower alkyl, arylalkoxy lower alkyl, alkanoyloxy lower alkyl or##STR6## where Z₁ is as previously defined; R₂₇ is hydrogen or R₂₄ andR₂₇ taken together with the carbon to which they are attached form C═Oor C═S;

and R and m are as defined hereinafter; ##STR7## where R₁ is aspreviously defined, and R₃ is hydrogen or --OCH₃ ; ##STR8## where R₁ isas previously defined; and R₄ is hydrogen, lower alkyl, lower alkoxy,hydroxy, tri(C₁ -C₆)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxylower alkyl, amino, mono- or dialkylamino, (C₁ -C₁₈)acyl amino, (C₁-C₁₈)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine, nitro,--O--C(═O)--(C₁ -C₁₈ straight or branched chain) alkyl or --C(═O)-aryl;

in which aryl is phenyl or ##STR9## where R₅ is hydrogen, lower alkyl,lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lowermonoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl,trifluoromethoxy; ##STR10## where R₁ and R₄ are as previously defined;##STR11## where either one of X_(y) or X_(z) is --C(═O)-- and the otheris --CH₂ --; and

R₅ ' is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine, orbromine; and

R₁ is as previously defined; ##STR12## where R₁ and R₄ are as previouslydefined; ##STR13## where A is --C(═O)--, --C(═S)--, --C(═CH₂)--,--C(═O)CH₂ --, --CH₂ CH₂ --, --CR₂₆ ═N--, or --CR₂₅ R₂₆ --;

R₂₅ is hydrogen, lower alkyl, hydroxy or alkanoyloxy;

R₂₆ is hydrogen or lower alkyl;

either one of B_(y) and B_(z) is CH or N and the other is CH;

U is O or S;

q is 1, 2, 3 or 4, and R₁ and R₄ are as previously defined; ##STR14##where R₁ is as previously defined; ##STR15## wherein R₁, R₄ and q are asdefined above; and R₂₈ is hydrogen, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl,phenyl or substituted phenyl; ##STR16## wherein R₁, R₄ and q are asdefined above; R₂₉ and R₃₀ are hydrogen, (C₁ -C₆)alkyl, aryl(C₁-C₆)alkyl, phenyl or substituted phenyl;

R₃₁ and R₃₂ are hydrogen, hydroxy, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl,phenyl, substituted phenyl, hydroxymethyl, or CHOR₃₃ where R₃₃ is (C₁-C₁₈)alkanoyl; or

either R₂₉ and R₃₀ taken together or R₃₁ and R₃₂ taken together with thecarbon group to which they are attached form a C═O or C═S group;##STR17## where R₁, R₄, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂ and q are as definedabove; ##STR18## where R₁, R₄, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂ and q are asdefined above; ##STR19## wherein R₁ and R₄ are previously defined and mis defined hereinafter; ##STR20## where R₁ is as previously defined; Q₂is S, NH, or --CH₂ --; and

R and m are as defined hereinafter; ##STR21## where R₁ is as previouslydefined; ##STR22## where R₁, and R₄ are as previously defined and m isas defined hereinafter; ##STR23## where R₁, R₄ are as previously definedand m is as defined hereinafter;

    --R.sub.1 --O--R.sub.12                                    (18)

where R₁₂ is selected from the group consisting of:

hydrogen,

alkyl,

--C(═O)--(C₁ -C₁₈ straight chain or branched) alkyl,

--C(═O)--NR₁₃ R₁₄,

--C(═O)--NR₁₅ R₁₆,

--S(═O)₂ --R₁₇, and ##STR24## where R₁₃ is selected from the groupconsisting of hydrogen and (C₁ -C₁₈)alkyl groups;

where R₁₄ is selected from the group consisting of hydrogen and (C₁-C₁₈)alkyl groups;

where NR₁₅ R₁₆ taken together form a ring structure selected from thegroup consisting of piperidinyl, morpholinyl and piperazinyl;

where R₁₇ is selected from the group consisting of lower alkyl and arylgroups;

where R₄ is previously defined and m is defined hereinafter;

    --R.sub.1 --NR.sub.18 R.sub.19                             (19)

where R₁₈ and R₁₉ are independently selected from the group consistingof:

hydrogen,

(C₁ -C₁₂ straight or branched chain) alkyl,

--C(═O)--O--(C₁ -C₁₈) alkyl,

--C(═O)--(C₁ -C₁₈) alkyl;

--C(═O)-pyridyl or ##STR25## where NR₁₈ R₁₉ taken together form a ringstructure selected from the group consisting of piperidinyl, morpholinyland piperazinyl; where the piperidinyl or piperazinyl ring is optionallysubstituted by ##STR26## where R₁, X, Y, p, R₄ and R₂₈ are as previouslydefined and m is defined hereinafter;

    --R.sub.1 --S--R.sub.12                                    (20)

where R₁ and R₁₂ are as previously defined; ##STR27## where R₁, R₄ andR₂₈ are as previously defined; and where

R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine,fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro,lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl,trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl,dialkylaminocarbonyl, formyl,

--C(═O)-alkyl,

--C(═O)--O-alkyl,

--C(═O)-aryl,

--C(═O)-heteroaryl,

--CH(OR₇)-alkyl,

--C(═W)-alkyl,

--C(═W)-aryl, and

--C(═W)-heteroaryl;

alkyl is (C₁ -C₁₈)alkyl;

aryl is as previously defined;

heteroaryl is ##STR28## Q₃ is --O--, --S--, --NH--, --CH═N--; W is CH₂or CHR₈ or N--R₉ ;

R₇ is hydrogen, alkyl, or alkanoyl;

R₈ is lower alkyl;

R₉ is hydroxy, alkoxy, or --NHR₁₀ ; and

R₁₀ is hydrogen, alkyl, (C₁ -C₃)acyl, aryl, --C(═O)aryl or--C(═O)heteroaryl, where aryl and heteroaryl are as defined above; and

m is 1, 2, or 3;

with the proviso that in formula (14) Z is not ##STR29## when X is--S--, Q₂ is --CH₂ --, Y is hydrogen, lower alkyl, lower alkoxy,halogen, hydroxy or trifluoromethyl, and p is 1 or 2;

with the proviso that in formula (4) R₄ is not H when R₁ is --(CH₂)₂₋₅--, Z is not ##STR30## X is --S--, Y is hydrogen, halogen, lower alkyl,lower alkoxy, hydroxy or trifluoromethyl, and p is 1 or 2;

with the proviso that in formula (14) Z is not ##STR31## when X is--NH-- or --N(R₂)--, Y is hydrogen, halogen, lower alkyl, lower alkoxy,hydroxy or trifluoromethyl and Q₂ is --CH₂ --;

with the proviso that in formula (14) Z is not ##STR32## when X is--O--, Q₂ is --CH₂ --, Y is hydrogen, lower alkyl, lower alkoxy, hydroxyor halogen, and p is 1 or 2;

with the proviso that in formula (14) Z is not ##STR33## when X is--S--, Q₂ is --CH₂ --, Y is hydrogen, halogen, lower alkyl, lower alkoxyor hydroxy, p is 1 or 2, R is hydrogen, and m is 1;

with the proviso that in formula (14) Z is not ##STR34## when X is--N(R₂)--, Q₂ is --CH₂ --, R is chlorine, fluorine, bromine, iodine,lower alkyl, lower alkoxy, lower alkyl thio, lower mono- ordialkylamino, amino, cyano, hydroxy, trifluoromethyl; R₂ is aryl; Y ishydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2;

with the proviso that in formula (14) Z is not ##STR35## when X is--NH-- or --N(R₂)--, where R₂ is lower alkyl, aryl lower alkyl, orphenylsulfonyl, Y is hydrogen, halogen, lower alkyl, lower alkoxy orhydroxy, p is 1 or 2 and Q₂ is --CH₂ --;

with the proviso that Y₂ is not the moiety of formula (8) when Z is##STR36## X is O, p is 1, and Y is hydrogen, lower alkyl, lower alkoxy,chlorine, fluorine, bromine, iodine or a hydroxyl group;

with the proviso that in formula (1) Z is not ##STR37## when X is O orS, Y is hydrogen, R is hydrogen, (C₁ -C₄)alkyl, chlorine, fluorine,bromine, iodine, cyano, (C₁ -C₄)alkoxy, aryl, --COOR₂₅ where R₂₅ is (C₁-C₄)alkyl;

with the proviso that in formula (1) Z is not ##STR38## when X is --S--,R₁ is --(CH₂)₂₋₅ --, R is H, and m=1; with the proviso that in formula(7) R₄ is not hydrogen when Y is 6-F, X is --O--, Z is ##STR39## and nis 2, 3 or 4; with the proviso that in formula (18) R₁₂ is not H when Zis ##STR40## X is --NH-- or --N(R₂)-- where R₂ is lower alkyl, aryllower alkyl, or phenylsulfonyl, Y is hydrogen, lower alkyl, loweralkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group and p is1 or 2;

with the proviso that in formula (18), R₁₂ is not H when X is --N(R₂)--,where R₂ is phenyl, Z is ##STR41## and Y is hydrogen, lower alkyl, loweralkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;

with the proviso that in formula (19), R₁₈ and R₁₉ are not lower alkylwhen Z is ##STR42## X is --N(R₂)-- and R₂ is aryl and Y is hydrogen,lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or ahydroxyl group;

with the proviso that in formula (19), when X is --O--, Z is ##STR43##and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine,bromine, iodine or a hydroxyl group, R₁₈ and R₁₉ are not lower alkyl;

with the proviso that in formula (19), R₁₈ and R₁₉ are not hydrogen whenR₁ is --(CH₂)₂₋₅ --, Z is ##STR44## X is --O--, and Y is 6-F; allgeometric, optical and stereoisomers thereof, or a pharmaceuticallyacceptable acid addition salt thereof.

This invention also provides compounds selected from formula I which aresuitable for acylation with (C₄ -C₁₈)carboxylic acids or reactivefunctional derivatives thereof to form highly lipophilic esters, amidesand carbamates, which compounds are also compounds of this invention.Such selected compounds possess a hydroxyl group attached to either analiphatic or aromatic carbon atom capable of forming the highlylipophilic esters of the invention, a primary or secondary nitrogen atomincluding the nitrogen at the 1-position of an indazole ring systemcapable of forming the highly lipophilic amides of the invention. Theprimary or secondary nitrogen atom may alternatively be acylated with a(C₄ -C₁₈)alkoxycarbonyl chloride to form a highly lipophilic carbamatederivative of the invention.

The invention also provides for the highly lipophilic compounds whichprovide long acting pharmaceutical effects when administered in the formof depot preparations.

This invention also provides a pharmaceutical composition, whichcomprises a compound of the invention and a pharmaceutically acceptablecarrier therefor. In one embodiment of the invention, the pharmaceuticalcomposition is an antipsychotic composition comprising a compound of theinvention in an amount sufficient to produce an antipsychotic effect.

In addition, this invention provides a method of treating psychoses,which comprises administering to a patient a pharmaceutically effectiveamount of a compound of the invention.

Further, this invention provides a method of sustained release of apharmaceutically effective amount of a lipophilic compound of theinvention in the form a depot preparation.

Finally, this invention provides a method of alleviating pain byadministering to a patient a pain-relieving amount of a compound of theinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The compounds of this invention are useful as antipsychotic drugs and asanalgesic agents. The compounds of the invention can contain a varietyof different substituents and chemical groups. As used herein, when theterm "lower" is mentioned in connection with the description of aparticular group, the term means that the group it is describingcontains from 1 to 6 carbon atoms.

The term "alkyl" as used herein refers to a straight or branched chainhydrocarbon group having up to 18 carbon atoms and containing nounsaturation, for example, methyl, ethyl, isopropyl, 2-butyl, neopentyl,n-hexyl or pentadecyl.

The term "alkoxy" as used herein refers to a monovalent substituentcomprising an alkyl group linked through an ether oxygen having its freevalence bond from the ether oxygen, e.g. methoxy, ethoxy, propoxy,butoxy, or pentoxy.

The term "alkylene" as used herein refers to a bivalent radical of alower branched or unbranched alkyl group having valence bonds on twoterminal carbons thereof, for example, ethylene (--CH₂ CH₂ --),propylene (--CH₂ CH₂ CH₂ --), or isopropylene (--CH(CH₃)CH₂ --).

The term "cycloalkyl" refers to a saturated hydrocarbon group possessingat least one carbocyclic ring, the ring containing from 3 to 10 carbonatoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclodecyl and the like.

The term "alkanoyl" refers to the radical formed by removal of thehydroxyl function from an alkanoic acid. More particularly, the term"alkanoyl" as used herein refers to an alkyl carbonyl moiety containingfrom 2 to 18 carbon atoms, e.g.

CH₃ --C(═O)--,

CH₃ --CH₂ --C(═O)--, etc.

Examples of alkanoyl groups are formyl, acetyl, propionyl,2,2-dimethylacetyl, hexanoyl, octanoyl, decanoyl, and the like.

The term "alkanoic acid" refers to a compound formed by combination of acarboxyl group with a hydrogen atom or alkyl group. Examples of alkanoicacids are formic acid, acetic acid, propanoic acid, 2,2-dimethylaceticacid, hexanoic acid, octanoic acid, decanoic acid, and the like.

The term "aryl lower alkyl" refers to compounds wherein "aryl" and"loweralkyl" are as defined above.

The term "lower alkylthio" refers to a monovalent substituent having theformula lower alkyl-S--.

The term "phenylsulfonyl" refers to a monovalent substituent having theformula phenyl-SO₂ --.

The term "acyl" refers to a substituent having the formula loweralkyl-C(═O)-- or CF₃ --C(═O)-- or aryl-C(═O)-- or heteroaryl-C(═O)--.

The term "lower monoalkylamino" refers to a monosubstituted derivativeof ammonia, wherein a hydrogen of ammonia is replaced by a lower alkylgroup.

The term "lower dialkylamino" refers to a disubstituted derivative ofammonia, wherein two hydrogens of ammonia are replaced by lower alkylgroups.

The term "acylamino" refers to a primary or secondary amine, wherein ahydrogen of the amine is replaced by an acyl group, where acyl is aspreviously defined.

The term "dialkylaminocarbonyl" refers to a derivative of an acid,wherein the hydroxyl group of the acid is replaced by a lowerdialkylamino group.

The term "aroyl" refers to a disubstituted carbonyl, wherein at leastone substituent is an aryl group, where "aryl" is as previously defined.

Unless otherwise indicated, the term "halogen" as used herein refers toa member of the halogen family selected from the group consisting offluorine, chlorine, bromine, and iodine.

Throughout the specification and appended claims, a given chemicalformula or name shall encompass all geometric, optical and stereoisomersthereof where such isomers exist.

A. COMPOUNDS OF THE INVENTION

The compounds of this invention can be represented by the followingformula: ##STR45## wherein X is --O--, --S--, --NH--, or --N(R₂)--;

R₂ is selected from the group consisting of lower alkyl, aryl loweralkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl andphenylsulfonyl groups;

p is 1 or 2;

Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine,iodine, lower alkoxy, trifluoromethyl, nitro, or amino;

Q₁ is selected from the group consisting of: ##STR46## where Z is##STR47## and Y₂ is selected from the group consisting of: ##STR48## inwhich (R₁) is --CR₂₄ R₂₇ --(CR₂₃ R₂₄)_(n) --CR₂₄ R₂₇ -- where n is0,1,2, or 3; or

--CHR₂₄ --CH═CH--CHR₂₄ --,

--CHR₂₄ --C.tbd.C--CHR₂₄ --,

--CHR₂₄ CH═CH--CR₂₃ R₂₄ --CHR₂₄ --,

--CHR₂₄ --CR₂₃ R₂₄ --CH═CH--CHR₂₄ --,

--CHR₂₄ --C.tbd.C--CR₂₃ R₂₄ --CHR₂₄ --, or

--CHR₂₄ --CR₂₃ R₂₄ --C.tbd.C--CHR₂₄ --,

the --CH═CH-- bond being cis or trans;

R₂₃ is hydrogen, (C₁ -C₁₈) linear alkyl, phenyl, hydroxy, (C₁-C₁₈)alkoxy, aryloxy, aryl(C₁ -C₁₈)alkyloxy, (C₁ -C₁₈)alkanoyloxy,hydroxy(C₁ -C₆)alkyl, (C₁ -C₁₈)alkoxy(C₁ -C₆)alkyl, phenyl(C₁-C₆)alkyloxy, aryl(C₁ -C₁₈)alkyloxy(C₁ -C₆)alkyl or (C₁-C₁₈)alkanoyloxy(C₁ -C₆)alkyl or ##STR49## where Z₁ is lower alkyl,--OH, lower alkoxy, --CF₃, --NO₂, --NH₂ or halogen; and

R₂₄ is hydrogen, (C₁ -C₁₈) linear alkyl, phenyl, hydroxy(C₁ -C₆)alkyl,(C₁ -C₁₈)alkoxy(C₁ -C₆)alkyl, phenyl(C₁ -C₆)alkyloxy, aryl(C₁-C₁₈)alkyloxy(C₁ -C₆)alkyl or (C₁ -C₁₈)alkanoyloxy(C₁ -C₆)alkyl or##STR50## where Z₁ is as previously defined; R₂₇ is hydrogen or R₂₄ andR₂₇ taken together with the carbon to which they are attached form C═Oor C═S; and

R and m are as defined hereinafter; ##STR51## where R₁ is as previouslydefined, and R₃ is hydrogen or --OCH₃ ; ##STR52## where R₁ is aspreviously defined; and R₄ is hydrogen, lower alkyl, lower alkoxy,hydroxy, tri(C₁ -C₆)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxylower alkyl, amino, mono- or dialkylamino, (C₁ -C₁₈)acyl amino, (C₁-C₁₈)alkanoyl, trifluoromethyl, chlorine, fluorine, bromine,--O--C(═O)--(C₁ -C₁₈ straight or branched chain) alkyl or --C(═O)-aryl;

in which aryl is phenyl or ##STR53## where R₅ is hydrogen, lower alkyl,lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lowermonoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl,trifluoromethoxy; ##STR54## where R₁ and R₄ are as previously defined;##STR55## where either one of X_(y) or X_(z) is --C(═O)-- and the otheris --CH₂ --; and R₅ ' is hydrogen, lower alkyl, lower alkoxy, chlorine,fluorine, or bromine; and R₁ is as previously defined; ##STR56## whereR₁ and R₄ are as previously defined; ##STR57## where A is --C(═O)--,--C(═S)--, --C(═CH₂)--, --C(═O)CH₂ --, --CH₂ CH₂ --, --CR₂₆ ═N-- or--CR₂₅ R₂₆ --;

R₂₅ is hydrogen, (C₁ -C₆)alkyl, hydroxy or (C₁ -C₁₈)alkanoyloxy;

R₂₆ is hydrogen or (C₁ -C₆)alkyl;

either one of B_(y) and B_(z) is CH or N and the other is CH;

U is O or S;

q is 1, 2, 3 or 4, and R₁ and R₄ are as previously defined; ##STR58##where R₁ is as previously defined; ##STR59## wherein R₁, R₄ and q are asdefined above; and R₂₈ is hydrogen, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl,phenyl or substituted phenyl; ##STR60## wherein R₁, R₄ and q are asdefined above; R₂₉ and R₃₀ are hydrogen, (C₁ -C₆)alkyl, aryl(C₁-C₆)alkyl, phenyl or substituted phenyl;

R₃₁ and R₃₂ are hydrogen, hydroxy, (C₁ -C₆)alkyl, aryl(C₁ -C₆)alkyl,phenyl, substituted phenyl, hydroxymethyl, or CHOR₃₃ where R₃₃ is (C₁-C₁₈)alkanoyl; or

either R₂₉ and R₃₀ taken together or R₃₁ and R₃₂ taken together with thecarbon group to which they are attached form a C═O or C═S group;##STR61## where R₁, R₄, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂ and q are as definedabove; ##STR62## where R₁, R₄, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂ and q are asdefined above; ##STR63## wherein R₁ and R₄ are previously defined and mis defined hereinafter; ##STR64## where R₁ is as previously defined; Q₂is S, NH, or --CH₂ --; and

R and m are as defined hereinafter; ##STR65## where R₁ is as previouslydefined; ##STR66## where R₁ and R₄ are as previously defined and m isdefined hereinafter; ##STR67## where R₁ and R₄ are as previously definedand m is defined hereinafter;

    --R.sub.1 --O--R.sub.12                                    (18)

where R₁₂ is selected from the group consisting of:

hydrogen,

alkyl,

--C(═O)--(C₁ -C₁₈ straight chain or branched) alkyl,

--C(═O)--NR₁₃ R₁₄,

--C(═O)--NR₁₅ R₁₆,

--S(═O)₂ --R₁₇, and ##STR68## where R₁₃ is selected from the groupconsisting of hydrogen and (C₁ -C₁₈) alkyl groups;

where R₁₄ is selected from the group consisting of hydrogen and (C₁-C₁₈) alkyl groups;

where NR₁₅ R₁₆ taken together form a ring structure selected from thegroup consisting of piperidinyl, morpholinyl and piperazinyl;

where R₁₇ is selected from the group consisting of (C₁ -C₁₈)alkyl andaryl groups;

where R₄ is previously defined and m is defined hereinafter;

    --R.sub.1 --NR.sub.18 R.sub.19                             (19)

where R₁₈ and R₁₉ are independently selected from the group consistingof:

hydrogen,

(C₁ -C₁₈ straight or branched chain) alkyl,

--C(═O)--O--(C₁ -C₁₈) alkyl,

--C(═O)--(C₁ -C₁₈) alkyl;

--C(--O)-pyridyl; ##STR69## where NR₁₈ R₁₉ taken together form a ringstructure selected from the group consisting of piperidinyl, morpholinyland piperazinyl;

where the piperidinyl or piperazinyl ring is optionally substituted by##STR70## where X, Y, p, R₁, R₄ and R₂₈ are as previously defined and mis defined hereinafter;

    --R.sub.1 --S--R.sub.12                                    (20)

where R₁ and R₁₂ are as previously defined; ##STR71## where R₁, R₄ andR₂₈ are as previously defined; and where

R is hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, chlorine,fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro,lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl,trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl,dialkylaminocarbonyl, formyl,

--C(═O)-alkyl,

--C(═O)--O-alkyl,

--C(═O)-aryl,

--C(═O)-heteroaryl,

--CH(OR₇)-alkyl,

--C(═W)-alkyl,

--C(═W)-aryl, and

--C(═W)-heteroaryl;

alkyl is (C₁ -C₁₈)alkyl;

aryl is as previously defined;

heteroaryl is ##STR72## Q₃ is --O--, --S--, --NH--, --CH═N--; W is CH₂or CHR₈ or N--R₉ ;

R₇ is hydrogen, alkyl, or alkanoyl;

R₈ is lower alkyl;

R₉ is hydroxy, alkoxy, or --NHR₁₀ ; and

R₁₀ is hydrogen, lower alkyl, (C₁ -C₁₈)acyl, aryl, --C(═O)-aryl or--C(═O)-heteroaryl, where aryl and heteroaryl are as defined above; and

m is 1, 2, or 3;

with the proviso that in formula (14) Z is not ##STR73## when X is--S--, Q₂ is --CH₂ --, Y is hydrogen, lower alkyl, lower alkoxy,halogen, hydroxy or trifluoromethyl, and p is 1 or 2;

with the proviso that in formula (4) R₄ is not H when R₁ is --(CH₂)₂₋₅--, Z is not ##STR74## X is --S--, Y is hydrogen, halogen, lower alkyl,lower alkoxy, hydroxy or trifluoromethyl, and p is 1 or 2;

with the proviso that in formula (14) Z is not ##STR75## when X is--NH-- or --N(R₂)--, Y is hydrogen, halogen, lower alkyl, lower alkoxy,hydroxy or trifluoromethyl and Q₂ is --CH₂ --;

with the proviso that in formula (14) Z is not ##STR76## when X is--O--, Q₂ is --CH₂ --, Y is hydrogen, lower alkyl, lower alkoxy, hydroxyor halogen, and p is 1 or 2;

with the proviso that in formula (14) Z is not ##STR77## when X is--S--, Q₂ is --CH₂ --, Y is hydrogen, halogen, lower alkyl, lower alkoxyor hydroxy, p is 1 or 2, R is hydrogen, and m is 1;

with the proviso that in formula (14) Z is not ##STR78## when X is--N(R₂)--, Q₂ is --CH₂ --, R is chlorine, fluorine, bromine, iodine,lower alkyl, lower alkoxy, lower alkyl thio, lower mono- ordialkylamino, amino, cyano, hydroxy, trifluoromethyl; R₂ is aryl; Y ishydrogen, halogen, lower alkyl, lower alkoxy or hydroxy, p is 1 or 2;

with the proviso that in formula (14) Z is not ##STR79## when X is--NH-- or --N(R₂)--, where R₂ is lower alkyl, aryl lower alkyl, orphenylsulfonyl, Y is hydrogen, halogen, lower alkyl, lower alkoxy orhydroxy, p is 1 or 2 and Q₂ is --CH₂ --;

with the proviso that Y₂ is not the moiety of formula (8) when Z is##STR80## O, p is 1, and Y is hydrogen, lower alkyl, lower alkoxy,chlorine, fluorine, bromine, iodine or a hydroxyl group;

with the proviso that in formula (1) Z is not ##STR81## when X is O orS, Y is hydrogen, R is hydrogen, (C₁ -C₄)alkyl, chlorine, fluorine,bromine, iodine, cyano, (C₁ -C₄)alkoxy, aryl, --COOR₂₅ where R₂₅ is (C₁-C₄)alkyl;

with the proviso that in formula (1) Z is not ##STR82## when X is --S--,R₁ is --(CH₂)₂₋₅ --, R is H, and m=1; with the proviso that in formula(7) R₄ is not hydrogen when Y is 6-F, X is --O--, Z is ##STR83## and nis 2, 3or 4; with that the proviso that in formula (18) R₁₂ is not Hwhen Z is ##STR84## X is --NH-- or --N(R₂)-- where R₂ is lower alkyl,aryl lower alkyl, or phenylsulfonyl, Y is hydrogen, lower alkyl, loweralkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group and p is1 or 2;

with the proviso that in formula (18), R₁₂ is not H when X is --N(R₂)--,where R₂ is phenyl, Z is ##STR85## and Y is hydrogen, lower alkyl, loweralkoxy, chlorine, fluorine, bromine, iodine or a hydroxyl group;

with the proviso that in formula (19), R₁₈ and R₁₉ are not lower alkylwhen Z is ##STR86## X is --N(R₂)-- and R₂ is aryl and Y is hydrogen,lower alkyl, lower alkoxy, chlorine, fluorine, bromine, iodine or ahydroxyl group;

with the proviso that in formula (19), when X is --O--, Z is ##STR87##and Y is hydrogen, lower alkyl, lower alkoxy, chlorine, fluorine,bromine, iodine or a hydroxyl group, R₁₈ and R₁₉ are not lower alkyl;

with the proviso that in formula (19), R₁₈ and R₁₉ are not hydrogen whenR₁ is --(CH₂)₂₋₅ --, Z is ##STR88## X is --O--, and Y is 6-F; allgeometric, optical and stereoisomers thereof, or a pharmaceuticallyacceptable acid addition salt thereof.

When the compounds of the invention are represented by the followingformula: ##STR89## where Q₁ is selected from the group consisting of:##STR90## the substituent X in formula (I) is selected from the groupconsisting of --O--, --S--, --NH--, or --N(R₂)--. When the substituent Xis --O--, the compounds of the invention contain a 1,2-benzisoxazolenucleus, and when X is --S--, the compounds of the invention contain a1,2-benzisothiazole nucleus. When X is --NH-- or --N(R₂)--, thecompounds of the invention contain the indazole nucleus.

When p in formula (I) is 1, the substituent Y is selected from the groupconsisting of hydrogen, lower alkyl, hydroxyl, halogen, lower alkoxy,--CF₃, --NO₂, and --NH₂. The substituent Y is preferably in the 5- or6-position of the ring. Moreover, in the preferred embodiments of theinvention, the substituent Y is hydrogen, hydroxy, chlorine, bromine, orfluorine, and in the particularly preferred compounds of the invention,Y is fluorine, especially in the 6-position of the ring.

When p in formula (I) is 2 and X is --O--, each Y substituent can beindependently selected from lower alkoxy, hydroxy or halogen groups,preferably methoxy groups.

When the substituent Y₂ has the formula (b)(1): ##STR91## and R₁contains unsaturation, R₁ preferably has the formula

    --CH.sub.2 --CH═CH--CH.sub.2 --.

When the substituent Y₂ has the formula (b)(3): ##STR92## thesubstituent R₄ is preferably hydrogen or (C₁ -C₆)alkyl carbonyl and n is3.

When the substitutent Y₂ has the formula (b)(4): ##STR93## thesubstitutent R₄ is preferably hydrogen or --C(═O)CH₃ and n is preferably1 or 2.

When the substituent Y₂ has the formula (b)(5): ##STR94## thesubstituent R₅ ' is preferably --OCH₃ and n is preferably 3.

When the substituent R₄ has the formula (b)(6): ##STR95## thesubstituent R₄ is preferably --C(═O)CH₃ and n is preferably 3.

When the substituent Y₂ has the formula (b)(7): ##STR96## thesubstituent R₄ is preferably hydrogen or methyl and n is preferably 2.

When the substituent Y₂ has the formula (b)(8): ##STR97## the value of nis preferably 3 or 4.

When the substituent Y₂ has the formula (b)(9): ##STR98## thesubstituent R₆ is preferably --CH₂ --CH═CH₂ --CH₂ -- when R₆ containsunsaturation.

When the substituent R is ##STR99## the substituent Q₃ is preferably--CH═N; and the substituent W is preferably CH₂, the substituent R₈ inCHR₈ is preferably CH₃, the substituent R, in N--R₉ is preferablyhydroxy, lower alkoxy, or NH₂, and the substituent R₁₀ in NHR₁₀ ispreferably hydrogen.

The value of n in the foregoing formulas can be 2, 3, 4, or 5, andpreferably is 2, 3, or 4. In the particularly preferred compounds of theinvention n is 2 or 3.

When X in the compounds of the invention is --N(R₂)--, the substituentR₂ is selected from the group consisting of lower alkyl, aryl loweralkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkanoyloxy and phenylsulfonylgroups.

The substituent Z can be ##STR100## in which case the compounds of theinvention are heteroarylpiperidine derivatives, or ##STR101## in whichcase the compounds are heteroarylpiperazine derivatives. When thesubstituent Q₁ has the formula ##STR102## the compounds of the inventionare heteroarylpyrrolidines. The preferred compounds of the invention arethe heteroarylpiperidines, i.e. compounds in which Z is ##STR103##

The compounds of the invention can contain one, two, or threeR-substituents. The substituent R can be hydrogen, lower alkyl, (C₁-C₁₈)alkoxy, hydroxyl, carboxyl, Cl, F, Br, I, amino, (C₁ -C₁₈)mono ordialkyl amino, --NO₂, lower alkyl thio, --OCF₃, cyano, acylamino, --CF₃,trifluoroacetyl (i.e. --C(═O)--CF₃), aminocarbonyl (i.e. --C(═O)--NH₂),dialkylaminocarbonyl,

formyl,

--C(═O)-alkyl,

--C(═O)--O-alkyl,

--C(═O)-aryl,

--C(═O)-heteroaryl, or

--CH(OR₇)-alkyl,

--C(═W)-alkyl,

--C(═W)-aryl, or

--C(═W)-heteroaryl;

alkyl is (C₁ -C₁₈) alkyl;

aryl is phenyl or ##STR104## where R₅ is hydrogen, lower alkyl, (C₁-C₆)alkoxy, hydroxy, Cl, F, Br, I, (C₁ -C₁₈)alkylamino, --NO₂, --CN,--CF₃, --OCF₃ ;

heteroaryl is ##STR105## Q₃ is --O--, --S--, --NH--, --CH═N--; W is CH₂or CHR₈ or N--R₉ ;

R₇ is hydrogen, alkyl, or alkanoyl;

R₈ is lower alkyl;

R₉ is hydroxy, alkoxy, or --NHR₁₀ ; and

R₁₀ is hydrogen, lower alkyl, (C₁ -C₁₈)acyl, aryl, --C(═O)-aryl or--C(═O)-- heteroaryl, where aryl and heteroaryl are as defined above;and

m is 1, 2, or 3.

When the compounds of the invention contain two or three R-substituents,each of the R-substituents can be independently selected from the abovesubstituents. Preferably, each of the R-substituents is selected fromthe group consisting of hydrogen, (C₁ -C₁₈) alkyl, (C₁ -C₁₈)alkoxy,hydroxyl, --COCF₃, (C₁ -C₁₈)alkanoyl, Cl, F, Br, I, (C₁ -C₃)alkylamino,--NO₂, --CF₃, --OCF₃,

--C(═O)-lower alkyl, and

--CH(OR₇)-lower alkyl.

The compounds of the present invention are prepared in the followingmanner. The substituents R, R₁, R₂, R₃, etc., X, Y, and Z and theintegers m, n, and p are as defined above unless indicated otherwise.

B. PREPARATION OF COMPOUNDS OF THE INVENTION

The compounds of the invention can generally be prepared by reacting apiperidine or a piperazine of the formula: ##STR106## or a pyrrolidineof the formula: ##STR107## under alkylating conditions with a compoundof the formula:

    HAL--Y.sub.2                                               (4)

where HAL is Cl, Br, or I. The procedures that can be employed forpreparing the piperidines, the piperazines, and the pyrrolidines and thealkylating agents identified by the above formulas will now be describedin detail.

Preparation of 3-(1-unsubstituted-4-piperazinyl)-1H-indazoles

Compounds of the formulae: ##STR108## for use in synthesizing theindazoyl-substituted piperazines of the invention can be prepared asfollows.

A substituted aryl ester of formula (7) is selected, ##STR109## whereR₁₁ is lower alkyl and Hal is a halogen selected from the groupconsisting of Cl, Br, and I. The ester of formula (7) is reacted withhydrazine, H₂ NNH₂, under standard hydrazide formation conditions.Typically, the reaction is carried out in a nonreactive solvent, e.g.ethanol, methanol, or toluene, at a temperature of ambient temperatureto the reflux temperature of the solvent for 4 to 16 hours to form ahydrazide of formula (8): ##STR110##

The hydrazide of formula (8) is reacted with a phenyl sulfonyl halide ofthe formula ##STR111## where Hal is a halogen selected from the groupconsisting of Cl and Br, to form a compound of the formula ##STR112##Typically this reaction is carried out in a basic solvent, such aspyridine or collidine, at a temperature of 0° to 30° C. for 2 to 16hours.

The compound of formula (10) in turn is reacted neat with thionylchloride at a temperature of 50° to 79° C. (reflux temperature) for 2 to16 hours to form a compound of formula (11) ##STR113## Compound (11) isreacted with a compound of formula (12), ##STR114## where R₁₁ is loweralkyl, under conventional nucleophilic reaction conditions, for examplein an inert solvent, such as tetrahydrofuran (THF), toluene, ordiethylether, at a temperature of 5° to 50° C. for 1 to 16 hours to forma compound having the formula ##STR115## The compound of formula (13) isthen reacted with a condensation agent, such as copper, copper-bronze,or cuprous oxide, in a solvent such as dimethylformamide,dimethylacetamide, or tetramethylurea, at a temperature of 120° to 177°C. for 1 to 16 hours to form a piperazine-substituted phenylsulfonylindazole of the formula ##STR116##

A cyano-substituted piperazine phenylsulfonyl indazole is then formed byreacting the compound of formula (14) with a conventional cyanationsource, such as a halo-cyanide, e.g. BrCN or ClCN, under conventionalcyanation conditions, typically in an inert solvent, e.g.dimethylsulfoxide (DMSO) or CHCl₃, at ambient temperature for 2 to 16hours to form a compound of formula ##STR117## The compound of formula(15) is then subjected to reduction by means of a metal hydride, e.g.lithium aluminum hydride (LiAlH₄). Typically the reduction is carriedout under standard reduction conditions in a solvent, such astetrahydrofuran or diethyl ether, at a temperature of 35° to 67° C. for6 to 16 hours to form a compound of formula (16): ##STR118##

A compound of formula (16) can be formed in an alternative manner byfirst reacting a compound of formula (14) with a strong base, such as ametal alcoholate, e.g. sodium methoxide, sodium ethoxide, or sodiumbutoxide, or with KOH in tetrahydrofuran to form a compound of formula(17): ##STR119## This reaction is typically carried out in a polarsolvent, such as for example CH₃ OH or C₂ H₅ OH, at a temperature ofambient to 50° C. for 1 to 16 hours.

Alternatively, the compound of formula (17) can be formed by reducingcompound (14) with LiAlH₄ under conditions as previously described.

The compound of formula (17) in turn can be reacted with a cyanationreagent, as previously described, to form a cyano substituted piperazineindazole of the formula ##STR120## which in turn can be reduced with ametal hydride, as previously described, to form a compound of formula(16).

In an alternative embodiment, a compound of formula (18) can be reactedwith an aqueous mineral acid, e.g. H₂ SO₄ or HCl, at a temperature of50° to 120° C. for 2 to 16 hours to form a compound of formula (16).

2. Preparation of 3-(1-unsubstituted-4-piperazinyl)-1,2-benzisoxazoles

A compound of the formula: ##STR121## can be prepared according toconventional techniques. Suitable procedures are described in J. Med.Chem. 1986, 29:359. Compounds of formula (19) are useful forsynthesizing the benzisoxazole substituted piperazines of the invention.

3. Preparation of 3-(1-unsubstituted-4-piperazinyl)-1,2-benzisothiazoles

A compound of the formula: ##STR122## for use in synthesizing thebenzisothiazole substituted piperazines of the invention can be preparedaccording to the techniques described in J. Med. Chem. 1986, 29:359,United Kingdom Patent (GB) 2 163 432 A and Tetrahedron Letters, Vol 34,No.41, pp 6525-6528, 1993.

4. Preparation of 3-(1-unsubstituted-4-piperidinyl)-1H-indazoles

A compound of the formula: ##STR123## for use in synthesizing theindazole-substituted piperidines of the invention can be prepared usingknown techniques. For example, suitable techniques are described insubstantial detail in U.S. Pat. No. 4,710,573.

5. Preparation of 3-(1-unsubstituted-4-piperidinyl)-1,2-benzisoxazoles

A compound of the formula: ##STR124## can be prepared by following theteachings from several sources. For example, U.S. Pat. No. 4,355,037contains a detailed description of compounds of formula (23) and ofmethods for preparing the compounds. Additional disclosure of methodsfor preparing the compounds of formula (23) can be found in U.S. Pat.No. 4,327,103 and in Strupczewski et al., J. Med. Chem., 28:761-769(1985). The compounds of formula (23) can be employed in the synthesisof the benzisoxazole substituted piperidines of the invention.

6. Preparation of 3-(1-unsubstituted-4-piperidinyl)-1,2-benzisothiazoles

Certain 3-(4-piperidinyl)-1,2-benzisothiazoles can be employed in thesynthesis of the N-(aryloxyalkyl)heteroaryl piperidines of theinvention. Specifically, a benzisothiazole of the formula: ##STR125##can be reacted with the alkylating agent previously described to formthe N-(aryloxyalkyl)heteroarylpiperidines of the invention. Compounds offormula (24) and their methods of preparation are described in detail inU.S. Pat. No. 4,458,076.

7. Preparation of alkylating agents

The compounds described in Sections 1-6 above can be reacted withalkylating agents as is known in the art. For example, when Y₂ is asdescribed in formula (1), an alkylating agent of the formula: ##STR126##is reacted to form the N-(aryloxyalkyl)heteroarylpiperidines,piperazines, and pyrrolidines of the invention. The alkylating agents offormula (4) and methods for preparing the alkylating agents aredescribed in U.S. Pat. No. 4,366,162. Additional disclosure can be foundin South African publication EA 86 14522. In addition, procedures formaking alkylating agents are described in the following Examples. Theseprocedures can be employed to make other alkylating agents for use inthis invention.

8. Alkylation of heteroarylpiperidines, piperazines, and pyrrolidines

The heteroarylpiperidines, piperazines, and pyrrolidines described inSections 1-6 above can be reacted under alkylating conditions with thealkylating agents described in Section 7 to form selected compounds ofthis invention. The reaction can be carried out by dissolving thereagents in an inert solvent, such as dimethylformamide, acetonitrile,or butanol, and allowing the reagents to react from a temperature of 50°C. to refluxing of the solvent in the presence of an acid receptor, suchas a base. Examples of suitable bases are alkali metal carbonates, suchas potassium carbonate, sodium carbonate, or sodium bicarbonate. Thereaction can be carried out with or without a catalytic amount of analkaline iodide, such as potassium iodide or sodium iodide, for a timesufficient to form a compound of formula (I) of the invention.Generally, the alkylation reaction is carried out for about 4 to about16 hours, depending on reactivity of the reagents. The reactiontemperature can vary from about 50° to about 120° C. The products can beisolated by treating the reaction product with water, extracting theproduct into an organic solvent that is immiscible in water, washing,drying, and concentrating the organic solvent to yield the free base,and then, if indicated, converting the resulting compound to an acidaddition salt in a conventional manner.

In addition, the compounds of formula 19 where R₁₈ R₁₉ are both hydrogenmay be prepared from the phthalimido compound of formula 7 by treatmentwith base such as, for example, hydrazine as is known in the art.

More specifically, certain of the compounds of the invention can besynthesized by the folowing methods:

A. Synthesis of Phthalimides

The phthalimido compounds of the invention of formula (25) can besynthesized ##STR127## in several ways.

1. Alkylation with an N-haloalkylphthalimide

The heterolarylpiperidines, piperazines and pyrrolidines described inSections 1-6 above are alkylated under known conditions using theappropriate haloalkylphthalirnide, preferably an N-bromoalkylphthalimide(26), in a nonprotic ##STR128## organic solvent such as acetonitrile inthe presence of a base such as potassium carbonate at a temperature offrom about room temperature to about 120° C., preferably from about 80°C. to about 100° C.

2. Reaction with a phthalic anhydride

The heteroarylpiperidines, piperazines and pyrrolidines described inSections 1-6 above are first reacted with a haloalkylnitrile to form thecorresponding substituted nitrile (27) wherein R is a substitutent asdefined for R₁ above. The reaction is carried out in a polar, nonproticorganic solvent such as ##STR129## acetonitrile in the presence of abase such as potassium carbonate at a temperature of from about roomtemperature to about 120° C., preferably from about 80° C. to about

The nitrile is then reduced, for example with lithium aluminum hydridein an organic solvent such as tetrahydrofuran at a temperature of fromabout 0° C. to about 80° C. preferably at about room temperature toyield the corresponding primary amine (28). ##STR130##

The amine(28) is reacted with phthalic anhydride or a substitutedphthalic anhydride or the corresponding phthalic acid under knownconditions, for example in dichloromethane or dimethylformamide attemperatures of from about 10° C. to about 150° C. to yield thecorresponding phthalimido compound. Preferred conditions for thereaction include dichloromethane at room temperature ordimethylformamide at 135° C.

B. Synthesis of isoindolines

The isoindolines of Formula (29) can be prepared by the followingroutes. ##STR131##

1. Condensation with an α,α'-dibromo-ortho-xylene

The amine (28) is reacted with an α,α'dibromo-ortho-xylene to obtain theisoindoline. The reaction is carried out in an organic solvent such asacetonitrile in the presence of a base such as potassium carbonate attemperatures of from about room temperature to about 150° C., preferablyfrom about 75° C. to about 100° C.

2. Reduction of a phthalimide

Alternatively, a phthalimido compound of the invention is reduced, forexample with lithium aluminun hydride in an organic solvent such astetrahydrofuran at a temperature of from about 0° C. to about 100° C.,preferably from about 70° C. to about 90° C.

C. Synthesis of tetrahydroquinolines and tetrahydroisoquinolines

The tetrahydroquinolines and tetrahydroisoquinolines of the inventioncan be prepared by alkylating the heteroarylpiperidine, piperazine andpyrrolidines (3, 3A) with the appropriate2-bromoacetyltetrahydroquinoline or 2-bromoacetyltetrahydroisoquinolinein the presence of a polar organic solvent such as acetonitrile in thepresence of a base such as potassium carbonate at temperatures of fromabout room temperature to about 150° C., preferably from about 75° C. toabout 100° C. to form the corresponding amide (30, 30a). ##STR132##

The amide (30, 30a) is reduced, for example with lithium aluminumhydride in an organic solvent such as tetrahydrofuran at a temperatureof from about 0° C. to about 80° C. preferably at about room temperatureto yield the alkyl compound.

9. Preparation of the "depot" compounds of the invention

Selected compounds of the invention possess a hydroxyl group attached toeither an aliphatic or aromatic carbon capable of forming the highlylipophilic esters of this invention or possess a primary or secondarynitrogen atom including the nitrogen at the 1-position of an indazolering system capable of forming the highly lipophilic amides of thisinvention. The primary or secondary nitrogen atom may alternatively beacylated with a C₄ -C₁₈ alkoxycarbonyl chloride to form a highlylipophilic carbamate derivative. Representatives of such alcohols andamines and their highly lipophilic derivatives are found in the Examplesof this invention.

It is known in the art that long acting derivatives of drugs may beobtained by such transformation. European Patent Publication No. 260,070discloses the prolonged action of haloperidol decanoate ester.International Publication No. WO 92/06089 discloses sustained releaseamide derivatives of sertindole.

Following are typical examples of compounds of the invention that can beprepared by following the techniques described above:

1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone;

1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone;

1-[4-[2-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanonefumarate;

1-[4-[4-[4-(1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanonefumarate;

1-[4-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanone;

4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-.alpha.-methylbenzenemethanol;

1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxyl-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(1H-indazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[4-[4-(6-chloro-1,2-benzisoxazol-3yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanonefumarate;

1-[4-[3-[4-(5-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;

6-fluoro-3-[1-[3-(2-methoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazolefumarate;

[4-[3-[4-(6-fluoro-1,2-benzoisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]phenylmethanone;

1-[4-[4-[4-(1H-indazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone;

1-[4-[2-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperdinyl]ethoxy]-3-methoxyphenyl]ethanone;

1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanonefumarate;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-methylphenyl]ethanone;

1-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-5-methylphenyl]ethanone;

N-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]acetamidehemifumarate;

6-chloro-3-(1-piperazinyl)-1H-indazole;

1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methylphenyl]ethanonehemifumarate;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone;

1-[4-[3-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone;

1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanone;

4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzoinitrile;

1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(1-benzoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanonesesquifumarate;

1-[4-[4-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]butoxyl-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanonehemifumarate;

1-[3,5dibromo-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone;

1-[4-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxyphenyl]ethanone;

6-fluoro-3-[1-(3-phenoxypropyl)-4-piperidinyl]-1,2-benzisoxazole;

1-[4-[2-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1,2-benzoisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methylmercaptophenyl]ethanone;

1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]phenylmethanone;

1-[3-bromo-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone;

3-[1-[3-[4-(1-ethoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolehydrochloride;

3-[1-[3-[4-(1-acetoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolefumarate;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy-3-methoxyphenyl]pentanone;

2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperdinyl]propoxy]-N-methylbenzenaminehemifumarate;

3-[1-[3-(4-bromo-2-methoxphenoxy)propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]propanone;

4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide;

1-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-(methylaimino)phenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-ethoxyphenyl]ethanone;

N-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-dimethylaminophenyl]ethanone;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-methoxyphenyl]ethanonehydrochloride;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2,2,2-trifluoroethanone;

4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-.alpha.-methylbenzenemethanol;

2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]anilinedihydrochloride;

N-[5acetyl-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide;

3-[1-[3-(4-ethyl-3-methoxyphenoxy)propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolehydrochloride;

1-[3,5dimethoxy-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone;

N-[3-[3-[4-(6-fluoro-1,2-benxoisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamidehemifumarate;

3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]aniline;

3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyaniline;

1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy-3-methylaminophenyl]ethanonefumarate;

N-[3-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]acetamide;

1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanonehydrochloride;

N,N-dimethyl-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanoneoxime;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]methoxyphenyl]-ethanoneoxime O-methyl ether;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanonehydrazone;

6-fluoro-3-[1-[3-[2-methoxy-4-(1-methylethenyl)phenoxy]propyl]-4-piperidinyl]-1,2-benzisoxazolehydrochloride;

(Z)-1-[4-[(4-chloro-2-butenyl)oxy]-3-methoxyphenyl]ethanone;

(Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-3-methoxyphenyl]ethanone;

(E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-hydroxyphenyl]ethanonehydrochloride;

(E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-benzyloxyphenyl]ethanone;

6-(3-chloropropoxy)-5-methoxyindole;

6-fluoro-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole;

6-fluoro-3-[1-[3-[(1H-indol-7-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazolehemifumarate;

6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole;

6-fluoro-3-[1-(2-pyrimidinoxy)propyl]-4-piperidinyl]-1,2-benzisoxazolefumarate;

6-aceto-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan;

2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan;

2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-1,4-benzodioxan;

6-(3-chloropropoxy)-7-methoxy-1-tetralone;

6-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-7-methoxy-1-tetralone;

N-(3-chloropropyl)-2-benzoxazolinone;

N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone;

N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-6-acetyl-2-benzoxazolinone;

N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]phthalimide;

1-(3-aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinedihydrochloride;

cis-2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)propyl)hexahydro-1H-isoindole-1,3-dionehydrochloride;

N-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butyl]phthalimide;

1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinedihydrochloride;

cis-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)butyl)hexahydro-1H-isoindole-1,3-dionehydrochloride;

1-[4-[[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]thio]-3-methoxyphenyl]ethanone;

4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-(2'-methoxyphenyl)butylpiperidinemaleate;

4-(4-bromobutyl)-1-(1,3-dithian-2-yl)ethylbenzene;

1-[4-(1,3-dithian-2-yl)ethyl]phenyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)butylpiperidine;

1-[4-(4'-acetophenyl)butyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-methoxyphenyl]ethanone;

(2,4-difluorophenyl)-[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxalate;

6-fluoro-3-[1-phenylmethyl)-3-pyrrolidinyl]-1,2-benzisoxazole fumarate;

(E)-1-[4-[(4-bromo-2-butenyl)oxy]-3-methoxyphenyl]ethanone;

4-(3-chloropropoxy)-3-methoxybenzaldehyde;

6-fluoro-3-(3pyrrolidinyl)-1,2-benzisoxazole hydrochloride;

1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-hydroxyphenyl]ethanone;

1-[3-acetylamino-4-(3-chloropropoxy)phenyl]ethanone;

N-[2-(3-hydroxypropoxy)phenyl]acetamide;

4-(3-chloropropoxy)-3-methoxybenzaldehyde;

(±)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylpropoxy]-3-methoxyphenyl]ethanone;

(S)-(+)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylpropoxy]-3-methoxyphenyl]ethanone;

(R)-(-)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylpropoxy]-3-methoxyphenyl]ethanone;

1-[4-[3-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2,2-dimethylpropoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-phenylpropoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-(3-chlorophenyl)propoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-(phenylmethyl)propoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-methypropoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methylpropoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methylbutoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-phenylbutoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1piperidinyl]-2-(2-phenylethy)butoxy]-3-methoxyphenyl]ethanone;

(±)-[4-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-methylethoxy]-3-methoxyphenyl]ethanone;

(E)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-methyl-2-butenyl]oxy]-3-methoxyphenyl]ethanone;

(Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methyl-2-butenyl]oxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-propyl-2-butynyl]oxy]-3-methoxyphenyl]ethanone;

(S)-(+)-1-[4-[3-[4-(6-fluoro-1H-indazol-3yl)-1-piperazinyl]-2-methylpropoxy]-3-methoxyphenyl]ethanone;

(R)-(-)-1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-2-methylpropoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-3-methylbutoxy]-3-methoxyphenyl]ethanone;

(±)-1-[4-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-phenypropoxy]-3-methoxyphenyl]ethanone;and

(±)-6-fluoro-3-[1-[3-(2-methyl-(2-methoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazole.

The compounds of the present invention are useful for treating psychosesby virtue of their ability to elicit an antipsychotic response inmammals. Antipsychotic activity is determined in the climbing mice assayby a method similar to those described by P. Protais, et al.,Psychopharmacol., 50:1 (1976) and B. Costall, Eur. J. Pharmacol., 50:39(1978).

Subject CK-1 male mice (23-27 grams) are group-housed under standardlaboratory conditions. The mice are individually placed in wire meshstick cages (4"×10") and are allowed one hour for adaption andexploration of the new environment. Then apomorphine is injectedsubcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for30 minutes. Compounds to be tested for antipsychotic activity areinjected intraperitoneally or given oral doses at various timeintervals, e.g. 30 minutes, 60 minutes, etc. prior to the apomorphinechallenge at a screening dose of 10-60 mg/kg.

For evaluation of climbing, 3 readings are taken at 10, 20, and 30minutes after apomorphine administration according to the followingscale:

    ______________________________________                                        Climbing Behavior                                                               Mice with: Score                                                            ______________________________________                                        4 paws on bottom (no climbing)                                                                     0                                                          2 paws on the wall (rearing) 1                                                4 paws on the wall (full climb) 2                                           ______________________________________                                    

Mice consistently climbing before the injection of apomorphine arediscarded.

With full-developed apomorphine climbing, the animals are hanging on tothe cage walls, rather motionless, over long periods of time. Bycontrast, climbs due to mere motor stimulation usually only last a fewseconds.

The climbing scores are individually totaled (maximal score: 6 per mouseover 3 readings) and the total score of the control group (vehicleintraperitoneally-apomorphine subcutaneously) is set to 100%. ED₅₀values with 95% confidence limits, calculated by a linear regressionanalysis, of some of the compounds of the present invention as well as astandard antipsychotic agent are presented in Table 1.

                  TABLE 1                                                         ______________________________________                                                                 CLIMBING                                                MOUSE ASSAY                                                                  COMPOUND (ED.sub.50 mg/kg, ip)                                              ______________________________________                                        1-[4-[3-[4-(1H-indazol-3-yl)-1-                                                                        0.98                                                   piperazinyl]propoxy]-3-methoxy-                                               phenyl]ethanone                                                               1-[4-[3-[4-(1,2-benzisoxazol-3-yl)- 0.67                                      1-piperidinyl]propoxy]-3-methoxy-                                             phenyl]ethanone                                                               1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol- 0.095                                  3-yl)-1-piperidinyl]propoxy]-3-methoxy-                                       phenyl]ethanone                                                               1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1- 1.6                                     piperidinyl]butoxy]-3-methoxyphenyl]                                          ethanone                                                                      1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 0.68                           piperidinyl]butoxy]-3-methoxyphenyl]ethanone                                  1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol- 0.16                                 3-yl)-1-piperidinyl]propoxy]-3-methoxy-                                       phenyl]ethanone hydrochloride                                                 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 0.29                                 piperidinyl]ethyl]-1,4-benzodioxan                                            (Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol- 0.61                              3-yl)-1-piperidinyl]-2-butenyl]oxy]-3-                                        methoxyphenyl]ethanone                                                        1-[4-(4'-acetophenyl)butyl]-4-(6-fluoro- 0.34                                 1,2-benzisoxazol-3-yl)piperidine                                              6-fluoro-3-[1-(3-hydroxypropyl)-4- 4.1                                        piperidinyl]-1,2-benzisoxazole                                                4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 3.31                                   1-piperidinyl]butyl decanoate fumarate                                        1-(3-aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)- 22.6                    piperidine dihydrochloride                                                    N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 5.0                                 1-piperidinyl]ethyl]phthalimide                                               N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 0.48                                1-piperidinyl]ethyl]phthalimide hydrochloride                                 6-fluoro-3-[1-[3-[(isoquinol-5-yl)oxy] 0.172                                  propyl]-4-piperidinyl]-1,2-benzisoxazole                                      sesquifumarate                                                                N-[2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)- 0.38                              1-piperidinyl]ethyl]phthalimide hydrochloride                                 N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 2.9                                 1-piperidinyl]ethyl]-3,6-difluorophthalimide                                  N-[2-[4-(6-fluoro-1H-indazol-3-yl)- 1.2                                       1-piperazinyl]ethyl]phthalimide                                               N-[2-[4-(6-fluoro-1H-indazol-3-yl)- 0.8                                       1-piperidinyl]ethyl]phthalimide hydrochloride                                 2,3-dihydro-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 0.64                    1-piperidinyl]ethyl]-3-methylene-1H-isoindol-1-one                            hydrochloride                                                                 2,3-dihydro-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 1.17                    1-piperidinyl]ethyl]-3-methyl-1H-isoindol-1-one                               hydrochloride                                                                 N-[2-[4-[(6-fluoro-1,2-benzoxazol-3-yl)-1-piperidinyl] 0.097                  ethyl]-4-aminophthalimide fumarate                                            N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] 1.6                   ethyl]-4-hydroxyphthalimide hydrochloride                                     2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl] 2.2                         ethyl]-2,3-dihydro-3-hydroxy-1H-isoindol-1-one                                hemifumarate                                                                  2-[2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1- 1.9                              piperidinyl]ethyl]-2,3-dihydro-1H-isoindol-1-one                              N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl] 0.37                        ethyl]-4-methylphthalimide dihydrochloride                                    N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-pipendinyl] 0.16                   ethyl]-3-methoxyphthalimide                                                   4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-[2-(2,3-dihydro- 0.36                    1H-isoindol-2-yl)ethyl]piperidine dihydrochloride                             3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] 0.61                  ethyl]-2-methyl-3H-quinazolin-4-one                                           4-(6-fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-1H- 0.25                       isoindol-2-yl)-ethyl]piperazine dimaleate                                     N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 0.7                               piperidinyl]-butyl]phthalimide hydrochloride                                  1-(1,2,3,4-tetrahydro-1H-isoquinolin-2-yl)-2- 6.25                            [4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-                           ethanone hydrochloride ethanolate                                             4-(6-fluoro-1H-indazol-3-yl)-1-[2-(5-fluoro-2,3- 0.16                         dihydro-1H-isoindol-2-yl)ethyl]piperazine dimaleate                           4-(6-fluoro-1H-indazol-3-yl)-1-[3-(2,3-dihydro- 0.46                          1H-isoindol-2-yl)propyl]piperazine dimaleate                                  N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 0.23                              piperidinyl]ethyl-1,2,3,4-tetrahydroisoquinoline                              difumarate                                                                    2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]- 2.33                    1-(2,3-dihydro-1H-isoindol-2-yl)ethanone fumarate                             4-(6-fluoro-1H-indazol-3-yl)-1-[2-(5-fluoro-2,3- 0.27                         dihydro-1H-isoindol-2-yl)ethyl]piperidine dimaleate                           N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- 1.19                              piperidinyl]ethyl]-1,2,3,4-tetrahydroquinoline fumarate                       4-(6-fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-5- 0.17                        methyl-1H-isoindol-2-yl)ethyl]piperazine difumarate                           4-(6-fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-4- 0.35                        methyl-1H-isoindol-2-yl)ethyl]piperazine difumarate                           4-(1H-indazol-3-yl)-1-[2-(2,3-dihydro-5-fluoro-1H- 1.32                       isoindol-2-yl)ethyl]piperazine dimaleate                                      N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl] 0.44                        ethyl]-1,2,3,4-tetrahydroisoquinoline dimaleate                               Clozapine (standard) 8.1                                                    ______________________________________                                    

Antipsychotic response is achieved when the compounds of the presentinvention are administered to a subject requiring such treatment as aneffective oral, parenteral, or intravenous dose of from 0.01 to 50 mg/kgof body weight per day. It is to be understood, however, that for anyparticular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and they do not, to any extent, limit thescope or practice of the invention.

Some of the compounds of the present invention are also useful asanalgetics due to their ability to alleviate pain in mammals. Theanalgetic utility is demonstrated in the phenyl p-quinone writhing assayin mice, a standard assay for analgesia: Proc. Soc. Exptl. Biol. Med.,95:729 (1957). Thus, for instance, the subcutaneous dose effecting anapproximately 50% inhibition of writhing (ED₅₀) in mice produced in thisassay is as shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                              INHIBITION OF                                              PHENYLQUINONE                                                                 INDUCED WRITHING                                                             COMPOUND ED.sub.50 mg/kg, sc                                                ______________________________________                                        1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]                                                         0.06                                                      propoxy]-3-methoxy-phenyl]ethanone                                            1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1- 0.17                                    piperidinyl]propoxy]-3-methoxyphenyl]                                         ethanone                                                                      1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 0.03                             1-piperidinyl]propoxy]-3-methoxyphenyl]                                       ethanone                                                                      Propoxyphene (standard) 3.9                                                   Pentazocine (standard) 1.3                                                  ______________________________________                                    

Analgesia is achieved when the compounds of the present invention areadministered to a subject requiring such treatment as an effective oral,parenteral, or intravenous dose of from 0.01 to 100 mg/kg of body weightper day. It is to be understood, however, that for any particularsubject, specific dosage regimens should be adjusted according to theindividual need and the professional judgment of the personadministering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and that they do not, to any extent, limit thescope or practice of the invention.

Effective amounts of the compounds of the present invention can beadministered to a subject by any one of several methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions.

The compounds of the present invention, while effective themselves, canbe formulated and administered in the form of their pharmaceuticallyacceptable addition salts for purposes of stability, convenience ofcrystallization, increased solubility, and the like. Preferredpharmaceutically acceptable addition salts include salts of mineralacids, for example, hydrochloric acid, sulfuric acid, nitric acid, andthe like; salts of monobasic carboxylic acids, for example, acetic acid,propionic acid, and the like; salts of dibasic is carboxylic acids, forexample, maleic acid, fumaric acid, and the like; and salts of tribasiccarboxylic acids, such as carboxysuccinic acid, citric acid, and thelike.

Effective quantities of the compounds of the invention can beadministered orally, for example, with an inert diluent or with anedible carrier. They can be enclosed in gelatin capsules or compressedinto tablets. For the purposes of oral therapeutic administration,compounds of the invention can be incorporated with an excipient andused in the form of tablets, troches, capsules, elixirs, suspensions,syrups, wafers, chewing gums, and the like. These preparations shouldcontain at least 0.5% of active compound of the invention, but can bevaried depending upon the particular form and can conveniently bebetween 4% to about 70% of the weight of the unit. The amount of activecompound in such a composition is such that a suitable dosage will beobtained. Preferred compositions and preparations according to thepresent invention are prepared so that an oral dosage unit form containsbetween 1.0-300 milligrams of the active compound of the invention.

Tablets, pills, capsules, troches, and the like can also contain thefollowing ingredients: a binder, such as microcrystalline cellulose, gumtragacanth, or gelatin; an excipient, such as starch or lactose; adisintegrating agent such as alginic acid, Primogel, corn starch, andthe like; a lubricant such as magnesium stearate or Sterotes; a glidantsuch as colloidal silicon dioxide; and a sweetening agent such assucrose; or saccharin, or a flavoring agent, such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it can contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms can contain variousmaterials that modify the physical form of the dosage unit, for example,as coatings. Thus, tablets or pills can be coated with sugar, shellac,or other enteric coating agents. A syrup can contain, in addition to theactive compounds, sucrose as a sweetening agent and certainpreservatives, dyes, colorings, and flavors. Materials used in preparingthese various compositions should be pharmaceutically pure and non-toxicin the amounts used.

For the purpose of parenteral therapeutic administration, the activecompound of the invention can be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but can be varied between 0.5 and about 50% of the weightthereof. The amount of active compounds in such compositions is suchthat a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

Solutions or suspensions can also include the following components: asterile diluent, such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol, or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates, or phosphates, and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampules, disposable syringes, or multiple dose vialsmade of glass or plastic.

The highly lipophilic esters, amides and carbamates of the presentinvention are capable of sustained release in mammals for a period ofseveral days or from about one to four weeks when formulated andadministered as depot preparations, as for example, when injected in aproperly selected pharmaceutically acceptable oil. The preferred oilsare of vegetable origin such as sesame oil, cottonseed oil, corn oil,coconut oil, soybean oil, olive oil and the like, or they are syntheticesters of fatty acids and polyfunctional alcohols such as glycerol orpropyleneglycol.

The depot compositions of the present invention are prepared bydissolving a highly lipophilic ester, amide or carbamate of the instantinvention in a pharmaceutically acceptable oil under sterile conditions.The oil is selected so as to obtain a release of the active ingredientover a desired period of time. The appropriate oil may easily bedetermined by consulting the prior art, or without undue experimentationby one skilled in the art.

An appropriate dose of a compound in accordance with this embodiment ofthe invention is from about 0.01 to 10 mg/kg of body weight perinjection. Preferably, the depot formulations of this invention areadministered as unit dose preparations comprising about 0.5 to 5.0 ml ofa 0.1 to 20% weight/weight solution of compound in the oil. It is to beunderstood that the doses set forth herein are exemplary only and thatthey do not, to any extent, limit the scope or practice of theinvention.

The following examples are for illustrative purposes only and are not tobe construed as limiting the invention. All temperatures are given indegrees Centigrade (°C.) unless indicated otherwise.

EXAMPLE 11-[4-[3-[4-(1H-Indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxy]phenyl]ethanone,

(A) 2-Bromobenzoic acid 2-phenylsulfonylhydrazide

To a solution of 2-bromobenzoic acid hydrazide (132 g) in pyridine (1.2L) cooled to about 10° C. with an ice bath, was added benzensulfonylchloride (78.3 ml). After complete addition, the reaction was stirred atambient temperature for four hours, and then poured intoice-hydrochloric acid to precipitate a yellow solid, 135 g. The materialwas recrystallized from isopropanol to yield 125 g of 2-bromobenzoicacid 2-phenylsulfonylhydrazide, m.p.=154-156° C.

(B) α-Chloro-2-bromobenzaldehyde phenylsulfonylhydrazone

A mixture of 2-bromobenzoic acid phenylsulfonylhydrazide (125 g, 350mmol) and thionyl chloride (265 ml) was stirred and refluxed for 2hours. After about 15 minutes of reflux, the solid went into solution.The reaction was permitted to cool, and then it was poured into hexane.The resultant white solid was collected to afford 124 g ofα-chloro-2-bromobenzaldehyde phenylsulfonylhydrazone, m.p.=120-122° C.

(C)1-[[(Phenylsulfonyl)hydrazono]-(2-bromophenyl)methyl]-4-methylpiperazine

To a stirred solution, under nitrogen, of α-chloro-2-bromobenzaldehydephenylsulfonylhydrazone (271.1 g; 720 mmol) in tetrahydrofuran (THF; 2L), was added dropwise N-methylpiperazine (159.7 g; 1600 mmol). Thereaction was stirred at ambient temperature for three hours, and thenpermitted to stand at ambient temperature for 16 hours. The reaction waschilled in an ice bath, and then filtered to remove the piperazinehydrochloride that was formed. The filtrate was concentrated to yield abrown gum. The gum was triturated with hot acetonitrile, the mixture wascooled in an ice bath, and when cold, was filtered to remove unwantedside product. The filtrate was then concentrated to afford 392.9 g of abrown gum of crude1-[[(phenysulfon-yl)hydrazono]-(2-bromophenyl)methyl]-4-methylpiperazine.

(D) 3-(4-Methyl-1-piperazinyl)-1-phenylsulfonyl-1H-indazole

A mixture of 1-[[(phenylsulfonyl)hydrazono]-(2-bromophenyl)methyl]-4-methylpiperazine (31.0 g, 80 mmol), copper bronze (3.1g), K₂ CO₃ (11.5 g), and dimethylformamide (500 ml), was stirred andrefluxed for 1.5 hours. The reaction was poured into water and theaqueous suspension was stirred vigorously with ethyl acetate. Thebiphasic mixture was filtered through Celite, and subsequently thelayers were separated. The aqueous portion was extracted with anotherportion of ethyl acetate, and the combined extracts were washed (H₂ O)and dried (MgSO₄). Concentration of the extract afforded a solid, whichupon trituration with ether gave 19.7 g of solid. The solid wasrecrystallized from isopropanol to afford 17.7 g (60%) of product,m.p.=158-161° C. An analytical sample was obtained by anotherrecrystallization from isopropanol (with charcoal treatment) to affordcolorless crystals of the indazole,3(4-methyl-1-piperazinyl)-1-phenylsulfonyl-1H-indazole, m.p.=160-161° C.

ANALYSIS: Calculated for C₁₈ H₂₀ N₄ O₂ S: 60.66% C 5.66% H 15.72% N;Found: 60.45% C 5.62% H 15.61% N

(E) 4-[1-(Phenylsulfonyl)-1H-indazol-3-yl]-1-piperazinecarbonitrile

To a stirred mixture of3-(4-methyl-1-piperazinyl)-1-phenylsulfonyl-1H-indazole (237 g, 0.67mole), K₂ CO₃ (102 g, 0.74 mole) and dimethylsulfoxide (DMSO, 2000 ml),under nitrogen, was added cyanogen bromide (72 g, 0.68 mmol) dissolvedin DMSO (525 ml). The reaction was stirred at ambient temperature for5.5 hours and was then poured into H₂ O (7 l). The solid, whichprecipitated from solution, was collected by filtration and was washedwell with H₂ O affording 168 g (68%) of product. A 5.2 g sample wasrecrystallized twice from ethanol-H₂ O yielding 4.0 g of4-[1-(phenylsulfonyl)-1H-indazol-3-yl]-1-piperazinecarbonitrile,m.p.=178-180° C.

ANALYSIS: Calculated for C₁₈ H₁₇ N₅ O₂ S: 58.85% C 4.66% H 19.06% N;Found: 59.01% C 4.63% H 19.09% N

(F) 3-(1-Piperazinyl)-1H-indazole

To a stirred mixture of4-[1-(phenylsulfonyl)-1H-indazol-3-yl]-1-piperazinecarbonitrile (163 g,0.44 mol) in tetrahydrofuran (2.0 l) was added, dropwise, lithiumaluminum hydride (880 ml; 0.88 mol of a 1M lithium aluminum hydridesolution in tetrahydrofuran). After complete addition, the reaction washeated to reflux and stirred for 6 hours, stirred at ambient temperaturefor one hour and allowed to sit at room temperature overnight. Thereaction was quenched by the careful dropwise addition of water. Afterno more hydrogen could be observed to evolve, the reaction was filteredand the lithium salt filter cake was washed well with tetrahydrofuran.The filtrate was combined with the filtrate of another run (all togetherthe starting material totaled 300 g, i.e. 820 mmol) and the combinedfiltrates were concentrated to afford 372 g of a yellow solid suspendedin water. An attempt was made to partition the product between water anddichloromethane, but the product proved to be only slightly soluble indichloromethane. Therefore, the biphasic product suspension was filteredthrough a course sintered funnel and the white product which wascollected was dried to afford 121 g. The two phases of the filtrate wereseparated and the water was extracted again with dichloromethane. All ofthe dichloromethane phases were combined, washed twice with water, driedwith magnesium sulfate, and concentrated to afford 41 g of a brownresidue. The residue was triturated with diethyl ether and filtered toafford 10 g of a beige solid, m.p.=139-150° C. The NMR and MS spectrawere consistent with the structure. Recrystallization of 10 g fromstoluene afforded 7.5 g of 3-(1-piperazinyl)-1H-indazole, m.p. 153-155°C.

(G) 3-(4-Methyl-1-piperazinyl)-1H-indazole

A stirred mixture of3-(4-methyl-1-piperazinyl)-1-phenylsulfonyl-1H-indazole (13.5 g, 38mmol), methanol (150 ml) and 25% CH₃ ONa in methanol (15.3 ml) wasstirred and refluxed for 2.5 hours. The reaction was concentrated toabout one-tenth its volume, and water was added to the mixture,resulting in a red solution. The solution was extracted withdichloromethane, the extract washed (H₂ O), dried (MgSO₄), and thesolvent was concentrated to afford 6.6 g of a rose-colored solid. Tworecrystallizations from toluene-hexane afforded 4.3 g (52%) of3-(4-methyl-1-piperazinyl)-1H-indazole as an off-white solid,m.p.=111-113° C.

ANALYSIS: Calculated for C₁₂ H₁₆ N₄ : 66.64% C 7.46% H 25.91% N; Found:66.83% C 7.42% H 25.69% N

(H) 4-(1H-indazol-3-yl)-1-piperazinecarbonitrile

To a stirred mixture of cyanogen bromide (5.3 g, 0.05 mol), K₂ CO₃ (7.1g) and dimethylsulfoxide (40 ml) was added, dropwise,3-(4-methyl-1-piperazinyl)-1H-indazole (11.0 g, 0.051 mol) dissolved indimethylsulfoxide (60 ml). The reaction was stirred at ambienttemperature for 1 hour, and then it was poured into water. The aqueoussuspension was extracted with ethyl acetate, the ethyl acetate waswashed (H₂ O), dried (MgSO₄), and concentrated to afford 7.8 g (67%) ofa yellow solid. This sample was combined with another and recrystallizedtwice from toluene to afford analytically pure4-(1H-indazol-3-yl)-1-piperazinecarbonitrile as a white solid,m.p.=120-122° C.

ANALYSIS: Calculated for C₁₂ H₁₃ N₅ : 63.42% C 5.76% H; Found: 63.04% C5.84% H

(I) 3-(1-Piperazinyl)-1H-indazole

A mixture of 4-(1H-indazol-3-yl)-1-piperazinecarbonitrile (8.0 g, 40mmol) and 25% H₂ SO₄ (100 ml) was stirred at reflux for 4.5 hours. Thereaction was cooled in an ice bath and made basic by the dropwiseaddition of 50% NaOH. The basic solution was extracted with ethylacetate. The ethyl acetate was washed with H₂ O, dried with MgSO₄, andconcentrated to afford 5.2 g (73% of the desired compound, as a solid.The solid was recrystallized twice from toluene to afford 3.0 g of3-(1-piperazinyl)-1H-indazole, m.p.=153-155° C.

ANALYSIS: Calculated for C₁₁ H₁₄ N₄ : 65.32% C 6.98% H 27.70% N; Found:65.21% C 6.99% H 27.80% N

(J)1-[4-[3-[4-(1H-Indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxy-4-phenyl]ethanone

A mixture of 3-(1-piperazinyl)-1H-indazole (4.0 g, 20 mmol), K₂ CO₃ (3.0g, 22 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22mmol), a few crystals of KI, and dimethylformamide (60 ml) was stirredat 90° C. for 5 hours. The reaction was poured into water, and theaqueous mixture was extracted with ethyl acetate. The extract was washed(brine), dried (MgSO₄), and the solvent was concentrated to afford awhite solid, which was triturated with diethyl ether and collected toyield 7.0 g of product. Two recrystallizations from absolute ethylalcohol yielded 5.3 g (64%) of analytically pure1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone,m.p.=155-157° C.

ANALYSIS: Calculated for C₂₃ H₂₈ N₄ O₃ : 67.62% C 6.91% H 13.72% N;Found: 67.45% C 6.74% H 13.56% N

EXAMPLE 21-[4-[3-[4-(1,2-Benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone

A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.8 g,20 mmol), K₂ CO₃ (5.2 g, 40 mmol),1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a fewcrystals of KI and dimethylformamide (60 ml) was stirred at 90° C. for16 hours. The reaction was poured into water and the aqueous mixture wasextracted with ethyl acetate. The extract was washed (water), dried(MgSO₄) and concentrated to afford a brown oil. The oil waschromatographed on a Waters Prep 500 utilizing silica gel columns andethyl acetate-diethylamine (2%), as eluent. Concentration of theappropriate fractions afforded 3.9 g of product as an off-white solid.Recrystallization from absolute ethyl alcohol afforded 2.6 g (33%) of1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone,m.p.=102-104° C., as colorless needles.

ANALYSIS: Calculated for C₂₄ H₂₈ N₂ O₄ : 70.56% C 6.91% H 6.86% N;Found: 70.73% C 6.93% H 6.85% N

EXAMPLE 31-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazolehydrochloride (5.1 g, 20 mmol), K₂ CO₃ (5.2 g, 40 mmol),1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), anddimethylformamide (60 ml) was heated at 90° C. for 16 hours. Thereaction was poured into water, and the aqueous mixture was extractedwith ethyl acetate. The ethyl acetate was washed (water), dried (MgSO₄)and concentrated to afford a moist solid. Recrystallization (twice) fromethyl alcohol afforded 5.0 g (58%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3methoxyphenyl]-ethanoneas a beige solid, m.p.=118-120° C.

ANALYSIS: Calculated for C₂₄ H₂₇ FN₂ O₄ : 67.60% C 6.38% H 6.57% N;Found: 67.47% C 6.40% H 6.53% N.

EXAMPLE 41-[4-[4-[4-(1,2-Benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone

A mixture of 3-(4piperidinyl)-1,2-benzisoxazole hydrochloride (4.3 g, 18mmol), K₂ CO₃ (5.5 g, 40 mmol), and1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.5 g, 18 mmol), anddimethylformamide (60 ml) was stirred and heated at 75° C. for 16 hours.The reaction was poured into water and was extracted with ethyl acetate.The ethyl acetate was washed (water), dried (MgSO₄), and the solventconcentrated to afford 7.2 g of a beige solid. Recrystallization (twice)from ethyl alcohol yielded 3.3 g (43%) of1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone,m.p.=99-101° C.

ANALYSIS: Calculated for C₂₅ H₃₀ N₂ O₄ : 71.11% C 7.16% H 6.63% N;Found: 70.76% C 7.24% H 6.58% N.

EXAMPLE 51-[4-[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone

A stirred mixture of 6-fluoro-3(4-piperidinyl)-1,2-benzisoxazolehydrochloride (5.1 g, 0.02 mol), K₂ CO₃ (5.2 g, 0.04 mol),1-[4(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.6 g, 22 mmol), anddimethylformamide (60 ml) was heated at 75° C. for 5 hours. The reactionwas poured into water, and the aqueous mixture was extracted with ethylacetate. The ethyl acetate was washed (water), dried (MgSO₄), and thesolvent was concentrated to yield initially an oil, which solidifiedupon standing. The solid was triturated with hexane and collected toafford 7.7 g of the product as a waxy solid. The compound waschromatographed on a Waters Prep 500 utilizing silica gel columns andeluting with dichloromethane/methanol (5%). Concentration of theappropriate fractions yielded 5.1 g of off-white solid1-[4-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanone,which when recrystallized from ethyl alcohol yielded 3.2 g (36%) offeathery-white needles, m.p.=88-90° C.

ANALYSIS: Calculated for C₂₅ H₂₉ FN₂ O₄ : 68.16% C 6.64% H 6.36% N;Found: 67.96% C 6.49% H 6.29% N.

EXAMPLE 61-[4-[2-[4-(1,2-Benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanonefumarate

A mixture of 3-(4piperidinyl)-1,2-benzisoxazole hydrochloride (4.8 g, 20mmol), K₂ CO₃ (5.2 g, 40 mmol),1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (5.0 g, 22 mmol), anddimethylformamide (90 ml) was heated at 90° C. for 16 hours. Thereaction was poured into water and the aqueous mixture was extractedwith ethyl acetate. The ethyl acetate was washed (water), dried (MgSO₄),and the solvent was concentrated to afford an oil. Upon standing, theoil solidified to afford a beige solid. The crude solid wasrecrystallized twice from ethyl alcohol to afford 5.9 g of an off-whitesolid. The solid was dissolved in ethyl acetate, and fumaric acid (1.2g, 1.1 equiv.) was added. The mixture was heated briefly on a steambath, and then stirred at ambient temperature for 2 hours. An initialgreen oil settled out and the supernatant solution was decanted. Etherwas added to the decantate and 4.0 g of a white fumarate salt wascollected. The salt was recrystallized twice from ethanol-ether to yield1.7 g (17%) of1-[4-[2-[4(1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanonefumarate, m.p.=127-129° C.

ANALYSIS: Calculated for C₂₃ H₂₆ N₂ O₄.C₄ H₄ O₄ : 63.52% C 5.92% H 5.49%N; Found: 63.00% C 5.87% H 5.42% N

EXAMPLE 71-[4-[4-[4-(1H-Indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanonefumarate

A stirred mixture of 3-(1-piperazinyl)-1H-indazole (4.0 g, 20 mmol), K₂CO₃ (5.3 g, 40 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.6g, 22 mmol), and dimethylformamide (60 ml) was heated at 75° C. for 6hours. The reaction was poured into water, and a white solidprecipitated from solution. The solid was collected and dried to afford7.2 g of the crude product. The crude solid was recrystallized twicefrom ethyl alcohol to yield 4.1 g of the free base, which was convertedto its fumarate salt by the addition of fumaric acid (1.1 g) to thecompound dissolved in refluxing acetone. The resulting fumarate salt(5.0 g) was recrystallized from ethyl alcohol to afford 3.8 g (35%) of1-[4-[4-[4-(1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanonefumarate, as a white solid, m.p.=163-165° C.

ANALYSIS: Calculated for C₂₄ H₃₀ N₄ O₃.C₄ H₄ O₄ : 62.44% C 6.36% H10.40% N; Found: 62.28% C 6.62% H 10.34% N.

EXAMPLE 81-[4-[2-[4-(6-Fluoro1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]-ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazolehydrochloride (5.1 g, 20 mmol), K₂ CO₃ (5.2 g),1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (5.0 g, 1022 mmol), anddimethylformamide (90 ml) was heated at 90° C. for 16 hours. Thereaction was poured into water, and the aqueous mixture was extractedwith ethyl acetate. The ethyl acetate was washed (water), dried (MgSO₄),and concentrated to afford 7.4 g of a yellow solid. The solid waschromatographed on a Waters Prep LC 500 utilizingdichloromethane/methanol (4%) as eluent, and subsequent concentration ofthe appropriate fraction afforded 4.0 g of a yellow solid. The solid wasrecrystallized from ethyl alcohol to yield 3.1 g (38%) of1-[4-[2-14-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxyl-3-methoxyphenyl]ethanone,as slightly yellow flakes, m.p.=132-134° C.

ANALYSIS: Calculated for C23H₂₅ FN₂ O₄ : 66.98% C 6.11% H 6.79% N;Found: 66.90% C 6.20% H 6.74% N.

EXAMPLE 94-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-.alpha.-methylbenzenemethanol

To a stirred mixture of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy-3-methoxy-phenyl]ethanone(4.0 g, 9.4 mmol) in methanol/tetrahydrofuran (60 ml, 1:1), was addedsodium borohydride (0.4 g, 10 mmol). After an initial evolution of gas,all insolubles went into solution. The reaction was stirred at ambienttemperature for 3 hours and TLC at this time showed a very slight amountof starting ketone. Therefore, another 0.1 g of sodium borohydride wasadded, and stirring was continued for an additional 0.5 hour. TLC nowshowed complete disappearance of starting material. The reaction wasconcentrated to an off-white residue, which was diluted with water andcollected to yield 3.4 g of alcohol. This was recrystallized fromtoluene (twice, with a charcoal treatment) to yield 2.7 g (67%) of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methoxy-α-methylbenzenemethanolas a white solid, m.p.=136-138° C.

ANALYSIS: Calculated for C₂₄ H₂₉ FN₂ O₄ : 67.27% C 6.82% H 6.54% N;Found: 67.59% C 6.89% H 6.47% N

EXAMPLE 101-[4-[3-[4-(1,2-Benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone

A mixture of 3-(4-piperidinyl)-1,2-benzisothiazole (3.0 g, 13.7 mmol),potassium carbonate (2.3 g, 16.5 mmol),1-[4-(3-chloropropoxy)-3methoxyphenyl]ethanone (4.0 g, 16.5 mmol),potassium iodide (200 mg) and acetonitrile (100 ml) was stirred atreflux under N₂ for 24 hours. The cooled reaction was filtered and thecake was washed well with acetonitrile. The filtrate was concentrated toan oily residue, which was partitioned between water and ethyl acetate.The ethyl acetate extract was washed well with water, dried with MgSO₄and concentrated to yield 6.1 g of a beige oil which solidified uponstanding. The product was triturated with diethyl ether and filtered togive 4.2 g of a beige solid. The compound was recrystallized from ethylalcohol to afford 3.5 g, and another recrystallization from ethylalcohol (utilizing decolonizing carbon) provided 2.4 g (41%) of1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone,m.p. 93-95° C.

ANALYSIS: Calculated for C₂₄ H₂₈ N₂ O₃ S: 67.90% C 6.65% H 6.60% N;Found: 67.89% C 6.61% H 6.59% N

EXAMPLE 111-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone

(A) 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone

To a stirred solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone(10.0 g, 41 mmol) in methylene chloride (120 ml) cooled to -50° C. (dryice-methanol) was added, dropwise, 1M boron tribromide in methylenechloride (123 ml, 120 mmol). The temperature was kept between -40° C.and -50° C. After complete addition, the reaction was permitted to reach-30° C., and the TLC checked (ca. 15 min. after final boron tribromidewas added). Saturated NaHCO₃ was added, dropwise, never allowing thetemperature to go above 0° C. during most of the addition. Whensufficient NaHCO₃ had been added to make the solution basic, the organiclayer was collected. The layer was washed with brine, dried (MgSO₄), andconcentrated to yield 8.1 g of dark brown oil, which solidified onstanding. This was chromatographed on a Waters Prep 500 LC (2 silicacolumns, 2% methanol-methylene chloride as eluent). Upon concentrationof the appropriate fractions, 5.8 g of a brown tacky solid wereobtained. This was recrystallized from isopropyl ether (with decantingof the yellow isopropyl ether supernatant from the dark brown oilyresidue) to give initially 2.5 g of a yellow solid. Concentration of themother liquor gave an additional 0.5 g, m.p.=110-113° C.

(B)1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone

A stirred mixture of 6-fluoro-3(4-piperidinyl)-1,2-benzisoxazole (2.8 g,13 mmol), NaHCO₃ (1.1 g), several crystals of KI,1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone, and acetonitrile (100ml) was refluxed for 16 hours. The reaction was poured into water, andthe aqueous mixture was extracted with ethyl acetate. The organicextract was washed (water), dried (MgSO₄), and the solvent wasconcentrated to afford 5.7 g of a thick yellow oil. The oil waschromatographed on a Waters Prep 500 LC on silica gel, eluting with 7%methanol/methylene chloride. Concentration of the appropriate fractionafforded a yellow oil, which upon standing yielded 3.5 g of the compoundas a pale, yellow solid. The solid was recrystallized from ethyl alcoholto afford 2.7 g (50%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-hydroxyphenyl]ethanoneas a pale yellow solid, m.p.=122-124° C.

ANALYSIS: Calculated for C₂₃ H₂₅ FN₂ O₄ : 66.98% C 6.11% H 6.79% N;Found: 66.97% C 6.20% H 6.69% N

EXAMPLE 121-[4-[3-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]-ethanone

A stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole (2.3 g, 100mmol), K₂ CO₃ (1.5 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone(2.8 g, 11 mmol), several crystals of KI and dimethylformamide (60 ml)was heated at 90° C. for 16 hours. The reaction was poured into H₂ O,and the aqueous suspension was extracted with ethyl acetate. The ethylacetate was washed (H₂ O), dried (MgSO₄) and concentrated to afford 5.0g of a yellow oil. The oil was chromatographed on a Waters Prep 500utilizing silica gel columns and eluting with methylenechloride/methanol (7%). Concentration of the desired fractions yielded2.0 g (46%) of an off-white solid. This sample was combined with 1.0 gof a previous sample, and this was recrystallized from toluene to afford2.6 g of1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-propoxy]-3-methoxyphenyl]ethanoneas a white solid, m.p.=135-137° C.

ANALYSIS: Calculated for C₂₃ H₂₇ FN₄ O₃ : 64.77% C 6.38% H 13.14% N;Found: 64.66% C 6.21% H 13.02% N

EXAMPLE 131-[4-[4-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]-ethanone

A stirred mixture of 6-fluoro-3(1-piperazinyl)-1H-indazole hydrochloride(5.0 g, 19 mmol), K₂ CO₃ (5.8 g) and1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.3 g, 21 mmol) anddimethylformamide (80 ml) was heated at 75° C. for 6 hours. The reactionwas poured into water, and an off-white solid formed from solution. Thesolid was collected and dried to yield 4.5 g of crude product. Thecompound was recrystallized from ethanol (3 times) to afford 3.0 g of anoff-white solid. The solid was chromatographed on a Waters Prep 500utilizing silica gel columns and eluting with methylenechloride/methanol (7%). Concentration of the appropriate fractionsafford 2.3 g of an off-white solid, which when recrystallized fromethanol yielded 1.9 g (26%) of analytically pure1-[4-[4-[4-(6-fluoro-1H-indazol-3yl)-1-piperazinyl]-butoxy]-3-methoxyphenyl]ethanone,m.p.=156-158° C.

ANALYSIS: Calculated for C₂₄ H₂₉ FN₄ O₃ : 65.44% C 6.64% H 12.72% N;Found: 65.38% C 6.49% H 12.60% N

EXAMPLE 14 1-[4-[3-[4-(1H-Indazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone

A mixture of 3-(4-piperidinyl)-1H-indazole (3.0 g, 15 mmol), K₂ CO₃ (1.6g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), afew crystals of KI and acetonitrile (100 ml) was stirred and refluxedfor 16 hours. The reaction was poured into water and a white solidseparated from solution. The solid was collected, dried and afforded 5.1g of product. Recrystallization from ethanol yielded 3.6 g of thecompound, which upon chromatography (preparative HPLC on silica gel,eluting with methylene chloride/methanol-9:1) gave 3.0 g (49%) of anoff-white solid. Recrystallization from ethanol afforded theanalytically pure1-[4-[3-[4-(1H-indazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]ethanoneas a white solid, m p.=171-173° C.

ANALYSIS: Calculated for C₂₄ H₂₉ N₃ O₃ : 70.74% C 7.17% H 10.31% N;Found: 70.52% C 7.27% H 10.42% N

EXAMPLE 151-[4-[3-[4-(6-Chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone

A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7g, 20 mmol), 1-[4-(3chloropropoxy)-3methoxyphenyl]ethanone (4.8 g, 20mmol), K₂ CO₃ (2.8 g), several crystals of KI and acetonitrile (120 ml)was refluxed for 16 hours. The reaction was filtered and the filtratewas concentrated to yield a solid-oil mixture. The residue waschromatographed on a Waters Prep 500 utilizing silica columns andeluting with methylene chloride/methanol (5%). Concentration of thedesired fractions yielded 3.2 g of a beige solid, which uponrecrystallization from ethanol afforded 2.7 g (31%) of1-[4-[3-[4-(6chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanoneas a beige solid, m.p.=116-118° C.

ANALYSIS: Calculated for C₂₄ H₂₇ C1N₂ O₄ : 65.08% C 6.14% H 6.32% N;Found: 65.35% C 6.22% H 6.28% N

EXAMPLE 161-[4-[4-[4-(6-Chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxyl-3-methoxyphenyl]ethanonefumarate

A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7g, 20 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.0 g, 20mmol), K₂ CO₃ (2.8 g) and acetonitrile (120 ml) was refluxed for 16hours. The reaction was allowed to cool, filtered, and the filtrate wasconcentrated to 9.9 g of a brown oil. The oil was chromatographed on aWaters Prep 500 utilizing silica gel columns and eluting with methylenechloride/methanol (5%). Concentration of the appropriate fractionsafforded 2.3 g of an off-white solid. The solid was dissolved in ethanoland fumaric acid (0.62 g, 1.1 eq.) was added. Upon concentration of theethanol, a crude, brown solid was collected, which was taken up inrefluxing acetone. Upon cooling, a white solid crystallized fromsolution yielding 2.2 g (19%) of1-[4-[4-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanonefumarate as a white solid, m.p.=139-141° C.

ANALYSIS: Calculated for C₂₅ H₂₉ ClN₂ O₄.C₄ H₄ O₄ : 60.78% C 5.80% H4.89% N; Found: 60.69% C 5.74% H 4.85% N

EXAMPLE 171-[4-[3-[4-(5-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone

A mixture of 5-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (2.4 g, 10 mmol),K₂ CO₃ (1.4 g), a few crystals of KI and acetonitrile (100 ml) wasstirred and refluxed for 8 hours. The reaction was poured into water andthe aqueous mixture was extracted with ethyl acetate. The ethyl acetateextract was washed (brine), dried (MgSO₄), and concentrated to afford4.0 g of a white solid. The solid was chromatographed on a Waters Prep500 HPLC utilizing silica gel columns and eluting with methylenechloride/methanol (5%). Concentration of the appropriate fractionsafforded 2.0 g (47%) of1-[4-[3-[4-(5-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanoneas a white crystalline solid, m.p.=103-105° C.

ANALYSIS: Calculated for C₂₄ H₂₇ FN₂ O₄ : 67.59% C 6.38% H 6.57% N;Found: 67.50% C 6.47% H 6.53% N

EXAMPLE 186-Fluoro3-[1-[3-(2-methoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazolefumarate

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.45g; 11.1 mmol), K₂ CO₃ (2.0 g), and 3-(2-methoxyphenoxy)propyl chloride(3.5 g, 17.4 mmol) in acetonitrile (40 ml) was heated at 90° C. for 4hours. At the end of the reaction, the solvent was removed, and thesolids were dissolved into dichloromethane (100 ml). The solution waswashed with water and brine, then dried over MgSO₄. The crude materialfrom the solution was combined with 1.2 g of crude material prepared inthe same fashion (using 0.5 g of starting material). The combinedmaterial was purified by flash chromatography on a silica gel column (49g, eluted with 0.5% diethylamine: 1% methanol:98.5% dichloromethane, 1L). The fractions containing the pure product were pooled andconcentrated down to a light oil (3.68 g). This oil was treated withfumaric acid (1.14 g, 9.8 mmol) in ethanol (13 ml). The6-fluoro-3-[1-[3-(2-methoxyphenoxy)-propyl]-4-piperidinyl]-1,2-benzisoxazolefumarate crystals obtained weighed 4.01 g (60%), m.p.=169-170° C.

ANALYSIS: Calculated for C₂₂ H₂₅ FN₂ O₃.C₄ H₄ O₄ : 62.39% C 5.84% H5.60% N; Found: 62.37% C 5.88% H 5.60% N

EXAMPLE 191-[3-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]phenylmethanone

A stirred mixture of 6-fluoro-3(4-piperidinyl)-1,2 benzisoxazole (2.01g; 9.13 mmol), K₂ CO₃ (2.0 g), and1-[3-(3-chloropropoxy)-4-methoxy-phenyl]phenylmethanone (3.93 g; 11.3mmol) and acetonitrile (50 ml) was heated at reflux for 4 hours. At theend of the reaction, the solvent was evaporated and the residue waspartitioned between water (150 ml) and dichloromethane (400 ml). Thedichloromethane solution was washed with water and brine (100 ml), driedover MgSO₄, then concentrated to an oil. The purification was done byflash chromatography over a silica gel column (SiO₂, 40 g; eluted withdichloromethane, 300 ml; 1% methanol in dichloromethane, 850 ml). Thematerial thus obtained as a colorless oil solidified on standing.Recrystallization from ethanol (150 ml) gave1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]-phenylmethanoneas white crystals, 3.07 g (63%), m.p.=140-141° C.

ANALYSIS: Calculated for C₂₉ H₂₉ FN₂ O₄ : 71.30% C 5.98% H 5.73% N;Found: 71.09% C 5.98% H 5.73% N

EXAMPLE 201-[4-[4-[4-(1H-indazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanon

A mixture of 3-(4-piperidinyl)-1H-indazole (3.2 g, 16 mmol),1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.0 g, 16 mmol), K₂ CO₃(2.2 g) and acetonitrile (100 ml) was stirred and refluxed for 6 hours.The reaction was poured into water and the resulting yellow solid thatformed was collected to afford 5.3 g of product. The compound wasrecrystallized from acetonitrile and then from ethyl acetate to yield3.0 g (45%) of a slightly yellow solid of1-[4-[4-[4-(1H-indazol-3-yl)-1-piperidinyl]-butoxy]-3-methoxyphenyl]ethanone,m.p.=133-135° C.

ANALYSIS: Calculated for C₂₅ H₃₁ N₃ O₃ : 71.23% C 7.41% H 9.97% N;Found: 70.85% C 7.61% H 9.81% N

EXAMPLE 211-[4-[2-[4-(6-Chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]-ethanone

A stirred mixture of 6-chloro-3-(4-piperidinyl)-1,2 benzisoxazole (4.6g, 19 mmol), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (4.3 g, 19mmol), K₂ CO₃ (2.8 g), a few crystals of KI and acetonitrile (120 ml)was refluxed for 16 hours. The reaction was filtered and the filtratewas concentrated to yield 8.0 g of yellow solid. The solid waschromatographed on a Waters Prep 500 LC (silica columns, eluting withmethylene chloride/methanol, 5%). Concentration of the appropriatefractions yielded 3.2 g of a light yellow solid, which uponrecrystallization from ethyl acetate afforded 2.3 g (28%) of1-[4-[2-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxyl-3-methoxyphenyl]ethanoneas a pale yellow solid, m.p.=133-135° C.

ANALYSIS: Calculated for C₂₃ H₂₅ ClN₂ O₄ : 64.41% C 5.88% H 6.53% N;Found: 64.35% C 5.87% H 6.41% N

EXAMPLE 22 3-(3-Bromopropoxy-4-methoxyphenyl)phenylmethanone

A solution of 3-hydroxy-4-methoxybenzophenone (4.6 g, 20 mmol) indimethylformamide (35 ml) was treated with sodium hydride (600 mg, 25mmol) at 0° C. for 20 minutes, then 1,3-dibromopropane (5 g, 24.7 mmol)was added in one portion. The mixture was heated at 90° C. for 1 hour,and then stirred at room temperature for 2 hours. At the end of thereaction, the mixture was poured into water (500 ml) and extracted withethyl acetate (400 ml). The ethyl acetate solution was washed withwater, brine and dried over anhydrous MgSO₄. The solvent was removed andthe crude oil was purified by flash chromatography over a silica gelcolumn (SiO₂, 85 g; eluted with 3:1 hexane:dichloromethane, 1.6 l; 3:7hexane: dichloromethane, 1.4 l). The pure product thus obtained weighed4.67 g, (66%) as an oil. Recrystallization twice from isopropyl ether(500 ml) gave analytically pure3-(3-bromopropoxy-4-methoxyphenyl)phenylmethanone (2.42 g), m.p.=81-83°C.

ANALYSIS: Calculated for C₁₇ H₁₇ BrO₃ : 58.47% C 4.91% H; Found: 58.63%C 4.82% H

EXAMPLE 231-[3-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanonefumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride(4.53 g, 20.5 mmol), K₂ CO₃ (4.5 g),1-[3-(3-chloropropoxy)phenyl]ethanone (6.4 g, 29 mmol) in acetonitrile(60 ml) was heated at reflux for 5 hours. At the end of the reaction,the solvent was removed and the residue was extracted intodichloromethane (300 ml). The inorganic insolubles were filtered off.The dichloromethane solution was concentrated to a small volume (10 ml)and purified on a flash chromatographic column (SiO₂, 75 g, eluted withdichloromethane, 900 ml; and 2% methanol in dichloromethane, 800 ml).The fractions containing the pure product were combined and concentratedto an oil (2.87 g, 35%). The oil was dissolved into ethanol and treatedwith a solution of fumaric acid (841 mg). Recrystallization (twice) fromethanol afforded 2.53 g of1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanonefumarate as white crystals, m.p.=172-174° C.

ANALYSIS: Calculated for C₂₂ H₂₅ FN₂ O₃.C₄ H₄ O₄ : 63.27% C 5.70% H5.47% N; Found: 63.00% C 5.63% H 5.43% N

EXAMPLE 241-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-methylphenyl]-ethanone

A stirred mixture of 6-fluoro-3(4-piperidinyl)-1,2 benzisoxazolehydrochloride (5.5 g, 21.6 mmol), K₂ CO₃ (3.5 g),1-[4-(3-bromopropoxy)-2-methylphenyl]-ethanone (4.83 g, 17.8 mmol) indimethylformamide (25 ml) and acetonitrile (75 ml) was heated at 120° C.for 5 hours. At the end of the reaction, the solvent was removed and theresidue was extracted into dichloromethane (300 ml) and the solution waswashed with water and brine. The organic solution was dried andevaporated to a crude oil. The purification was done by flashchromatography over a silica gel column (80 g, eluted withdichloromethane, 1 l; 1% methanol: dichloromethane, 1.2 l; 2%methanol:dichloromethane, 1.2 l). The purest fractions were combined andafforded 2.91 g of solid. Recrystallization from dichloromethane andethanol gave1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-methylphenyl]ethanoneas off-white crystals: 2.42 g, m.p.=113-114° C.

ANALYSIS: Calculated for C₂₄ H₂₇ FN₂ O₃ : 70.22% C 6.63% H 6.82% N;Found: 70.13% C 6.63% H 6.77% N

EXAMPLE 251-[2-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-5-methylphenyl]-ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride(2.87 g, 11.23 mmol), K₂ CO₃ (2.5 g),1-[2-(3-bromopropoxy)-5-methylphenyl]ethanone (3.74 g, 13.8 mmol) indimethylformamide (10 ml) and acetonitrile (50 ml) was heated at 95° C.for 6 hours. At the end of the reaction, the solvent was concentratedand the mixture was extracted into dichloromethane (300 ml). The organicsolution was washed with water and brine, dried over MgSO₄, thenconcentrated down to a crude oil. The purification was done by flashchromatography over a silica gel column (SiO₂, 60 g, eluted with 1% CH₃OH:dichloromethane: 1.2 l; 3% CH₃ OH:dichloromethane: 600 ml). Thematerial thus obtained was crystallized from a small volume of ether andhexane to provide 2.13 g (46%) of off-white1-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-iperidinyl]propoxy]-5-methylphenyl]ethanone,m.p.=92-93° C.

ANALYSIS: Calculated for C₂₄ H₂₇ FN₂ O₃ : 70.22% C 6.63% H 6.82% N;Found: 70.21% C 6.69% H 6.81% N

EXAMPLE 26N-[3-[3-[4-(6-Fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]acetamidehemifumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride(3.94 g, 15.4 mmol), K₂ CO₃ (3.67 g, 26.6 mmole),N-[3-(3-bromopropoxy)-4-methoxyphenyl]acetamide (5.56 g, 18.6 mmol) indimethylformamide (75 ml) and acetonitrile (100 ml) was heated at 100°C. for 3 hours. At the end of the reaction, the solvent was concentratedand the mixture was extracted into dichloromethane (500 ml). The organicsolution was washed with water (500 ml) and brine (400 ml), dried, thenconcentrated to a crude oil. The purification was effected by flashchromatography over a silica gel column (SiO₂, 65 g, eluted with 1% CH₃OH:dichloromethane, 1.2 l; and 3% CH₃ OH:dichloromethane, 500 ml). Thematerial thus obtained weighed 2.33 g (34.3%) as an oil. This materialwas dissolved in ethanol and treated with a solution of fumaric acid(661 mg) in ethanol. The N-[3-[3-[4-(6-fluoro-1,2benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]acetamidehemifumarate was obtained as off-white crystals weighing 2.17 g,m.p.=205-206° C.

ANALYSIS: Calculated for C₂₄ H₂₈ FN₃ O₄.0.5 C₄ H₄ O₄ : 62.50% C 6.05% H8.41% N; Found: 62.30% C 6.05% H 8.32% N

EXAMPLE 27 6-Chloro-3-(1-piperazinyl)-1H-indazole

To a stirred suspension of4-(6-chloro-1-phenylsulfonyl-1H-indazol-3-yl)-1-piperazinecarbonitrile(192.5 g, 479 mmol) in dry tetrahydrofuran (3.5 l) under N₂ was added,dropwise, LiAlH₄ (958 ml of a 1.0M solution of lithium aluminum hydridein tetrahydrofuran; 958 mmol). After complete addition, the reaction washeated to reflux and stirred under N₂ for 4 hours. The reaction wascooled to 4° in an ice-salt bath and the excess lithium aluminum hydridewas destroyed by the careful, dropwise addition of H₂ O. The mixture wasstirred vigorously for an additional 30 minutes and was then filteredthrough a coarse sintered glass funnel. The filter cake was washed wellwith tetrahydrofuran (3×500 ml) and then with methanol (2×500 ml) andthe filtrate was concentrated to yield 151.0 g of a beige gum.Trituration with diethyl ether afforded a solid, which was collected anddried to give 75.0 g (66%) of the desired indazole. A 4.0 g sample wasrecrystallized from toluene to yield 3.2 g, which was recrystallizedagain from toluene (utilizing decolonizing carbon) to provide 2.1 g(35%) of a beige, 6-chloro-3-(1-piperazinyl)-1H-indazole solid,m.p.=135-137° C.

ANALYSIS: Calculated for C₁₁ H₁₃ ClN₄ : 55.82% C 5.54% H 23.67% N;Found: 55.91% C 5.54% H 23.41% N

EXAMPLE 281-[4-[3-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (3.5 g, 16mmol), K₂ CO₃ (2.2 g), 1-[4(3-chloropropoxy)-3-methoxyphenyl]ethanone(3.8 g, 16 mmol) and acetonitrile (90 ml) was refluxed for 16 hours. Thereaction was poured into water and the resulting white solid, whichprecipitated from solution, was collected to afford 5.5 g of the desiredproduct. The compound was recrystallized from dimethylformamide (twice)to afford 3.0 g (44%) of1-[4-[3-[4(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]propoxy]-methoxyphenyl]ethanoneas a white solid, m.p.=202-204° C.

ANALYSIS: Calculated for C₂₄ H₂₈ FN₃ O₃ : 67.75% C 6.63% H 9.88% N;Found: 67.59% C 6.61% H 9.96% N

EXAMPLE 291-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methylphenyl]-ethanonehemifumarate

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazolehydrochloride (3.0 g; 11.7 mmol), K₂ CO₃ (3.0 g), and1-[4-(3-bromopropoxy)-3-methylphenyl]ethanone (3.19 g) indimethylformamide (20 ml) and acetonitrile (50 ml) was heated at 95° C.for 4 hours. At the end of the reaction, the solvent was concentrateddown to about 30 ml, then partitioned between water (200 ml) anddichloromethane (300 ml). The dichloromethane solution was separated andwashed with water and brine, then dried over MgSO₄. The crude productfrom the evaporated solution was purified by flash chromatography over asilica gel column (SiO₂, 60 g, eluted with 1% methanol indichloromethane, 600 ml; 2% methanol in dichloromethane, 600 ml). Thematerial thus obtained was a light yellow oil, weight: 2.07 g (43%).This oil was dissolved in ethanol and treated with a solution of fumaricacid (585 mg) in ethanol. The1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]-3-methylphenyl]ethanonehemifumarate crystals formed on cooling at 0° C. This was collected andweighed 1.5 g, m.p.=185-187° C.

ANALYSIS: Calculated for C₂₄ H₂₇ FN₂ O₃.0.5 C₄ H₄ O₄ : 66.65% C 6.24% H5.98% N; Found: 66.69% C 6.23% H 5.95% N

EXAMPLE 301-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.27 g, 14.8mmol), K₂ CO₃ (3 g), 1-[4-(3-bromopropoxy)phenyl]ethanone (4.5 g, 17.5mmol) in acetonitrile (60 ml) was heated at reflux for 4 hours. Thesolvent was removed. The residue was dissolved in dichloromethane (300ml) and washed with water and brine, then dried over MgSO₄. The crudeproduct from the evaporated solution was purified by flashchromatography (SiO₂, 60 g; eluted with 1% methanol in dichloromethane,1 liter). The purest fractions were combined and gave 2.8 g, 48%, of1-[4-[3-[4-(6fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy)phenyl]ethanone,m.p.=111-112° C.

ANALYSIS: Calculated for C₂₃ H₂₅ FN₂ O₃ : 69.68% C 6.36% H 7.07% N;Found: 69.80% C 6.38% H 7.07% N

EXAMPLE 311-[4-[3-[4-(6-Chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]-ethanone

A mixture of 6-chloro-3-(1-piperazinyl)-1H-indazole (3.4 g, 14 mmol), K₂CO₃ (2.5 g, 18 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone(3.8 g, 16 mmol), KI (200 mg), and acetonitrile (125 ml) was stirred atreflux under N₂ for 30 hours. After standing at room temperature for 40hours, the reaction was filtered and the filter cake was washed wellwith acetonitrile. The filtrate was concentrated to an oily solid, whichwas partitioned between water and ethyl acetate. The ethyl acetateextract was washed with water, dried with MgSO₄, and concentrated toyield 6.9 g of a dark oil, which solidified after 2 days under vacuum.The product was purified by preparative HPLC (Waters Associates PrepLC/system 500 utilizing 2 silica gel columns and 6% methanol/methylenechloride as eluent) to yield 4.2 g. The material was recrystallized fromethanol to yield 3.4 g of glistening, beige,1-[4-[3-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]-ethanonecrystals, m.p.=132-134° C.

ANALYSIS: Calculated for C₂₃ H₂₇ ClN₄ O₃ : 62.37% C 6.14% H 12.65% N;Found: 62.49% C 6.16% H 12.60% N

EXAMPLE 321-[4-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]butoxyl-3-methoxyphenyl]ethanone

A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol),1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.0 g, 20.0 mmol), K₂ CO₃(3.0 g, 21.8 mmol), KI (200 mg), and acetonitrile (125 ml) was stirredat reflux under N₂ for 5 hours. Most of the solvent was removed in vacuoand the resultant gummy residue was partitioned between ethyl acetateand water. The organic extract was washed with water, dried with MgSO₄,and concentrated to yield 7.8 g. Purification by preparative HPLC(Waters Associates Prep LC/System 500, utilizing 2 silica gel columnsand 4% methanol-methylene chloride as eluent) afforded 6.5 g of a damp,off-white solid. The product was recrystallized twice from toluene toprovide 3.1 g (39%) of1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanoneas a white solid, m.p.=114-116° C.

ANALYSIS: Calculated for C₂₄ H₂₉ N₃ O₃ S: 65.58% C 6.65% H 9.56% N;Found: 65.74% C 6.66% H 9.54% N

EXAMPLE 334-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-benzonitrile

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6mmol), K₂ CO₃ (2.8 g), 4-(3bromopropoxy)-3-methoxybenzonitrile (4.0 g,14.8 mmol) in acetonitrile (70 ml) was heated at reflux for 3 hours. Atthe end of the reaction, the solvent was removed on a rotary evaporator.The organic material was extracted into dichloromethane (250 ml) and theinorganics were filtered off. The dichloromethane solution wasconcentrated to a crude oil. The purification was done by flashchromatography over a silica gel column (SiO₂, 55 g; eluted withdichloromethane, 600 ml; 1% methanol in dichloromethane, 600 ml). Thematerial thus obtained was crystallized from a small amount ofdichloromethane. Recrystallization from ethanol (25 ml) provided 3.8 g(68%) of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzonitrileas white crystals, m.p.=107-108° C.

ANALYSIS: Calculated for C₂₃ H₂₄ FN₃ O₃ : 67.47% C 5.91% H 10.26% N;Found: 67.32% C 5.90% H 10.24% N

EXAMPLE 341-[4-[4-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperidinyl]butoxyl-3-methoxyphenyl]-ethanone

A stirred mixture of 6-fluoro-3(4-piperidinyl)-1H-indazole (1.9 g, 8.6mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (2.6 g, 8.6 mmol),K₂ CO₃ (1.2 g), and acetonitrile (75 ml) was refluxed for 6 hours. Thereaction was poured into water and a white solid settled from solution.This was collected, dried and afforded 3.2 g of product. The product wasrecrystallized from ethanol to yield 2.7 g (71%) of1-[4-[4-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]butoxy]-3-methoxy-phenyl]ethanoneas glistening white flakes, m.p.=158-160° C.

ANALYSIS: Calculated for C₂₅ H₃₀ FN₃ O₃ : 68.32% C 6.88% H 9.56% N;Found: 68.00% C 6.93% H 9.51% N

EXAMPLE 351-[4-[3-[4-(1-Benzoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxy-phenyl]ethanonesesquifumarate

A mixture of1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanone(3.2 g, 7.5 mmol) and benzoyl chloride (15 ml) was heated on a steambath for 15 minutes. The reaction was allowed to cool and ether wasadded. The insoluble off-white compound was harvested to yield 4.4 g ofthe product as a hydrochloride salt. The salt was converted to free basewith aqueous ammonium hydroxide, and after extractive workup withmethylene chloride, 3.0 g of the free base was isolated as a whitesolid. The free base was dissolved in ethyl acetate and fumaric acid(0.72 g, 1.1 eq.) was added and the mixture heated on the steam bath for15 min. After standing at ambient temperature for 4 days, 2.0 g of anoff-white fumarate salt was collected, while concentration of thefiltrate afforded an additional 1.0 g of the salt. Recrystallization,first from ethyl acetate, and then from ethanol yielded 1.4 g (26%) of1-[4-[3-[4-(1-benzoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3methoxyphenyl]ethanonesesquifumarate, m.p.=138-140° C.

ANALYSIS: Calculated for C₃₀ H₃₁,FN₄ O₄.1.5 C₄ H₄ O₄ : 61.35% C 5.29% H7.95% N; Found: 61.68% C 5.31% H 8.25% N

EXAMPLE 361-[4-[4-[4-(6-Chloro-1H-indazol-3-yl)-1-piperazinyl]butoxyl-3-methoxyphenyl]-ethanone

A mixture of 6-chloro-[3-(1-piperazinyl)]-1H-indazole (4.0 g, 17 mmol),K₂ CO₃ (2.8 g, 20 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone(5.7 g, 19 mmol), KI (100 mg) and acetonitrile (125 ml) was stirred atreflux under nitrogen for 18 hours. The cooled reaction was poured intowater and the resultant off-white solid was collected by filtration anddried to yield 7.0 g. The compound was recrystallized twice from tolueneto yield 6.2 g. Further purification by preparative HPLC (WatersAssociates Prep LC/System 500, utilizing 5% methanol/methylene chlorideas eluent and 2 silica gel columns) afforded 5.3 g of glistening, beigecrystals, which were recrystallized four times from toluene to yield 3.1g of a white solid. Analytically pure material was obtained by asubsequent recrystallization from dimethylformamide to afford 2.5 g(32%) of1-[4-[4-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanoneas an off-white powder, m.p.=189-191 9C.

ANALYSIS: Calculated for C₂₄ H₂₉ ClN₄ O₃ : 63.08% C 6.40% H 12.26% N;Found: 62.86% C 6.57% H 12.49% N

EXAMPLE 371-[4-[3-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]-ethanonehemifumarate

A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol),K₂ CO₃ (3.0 g, 21.8 mmol), KI (200 mg),1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 20.0 mmol), andacetonitrile (125 ml) was stirred at reflux under N₂ for 26 hours. Thecooled reaction was filtered and the filter cake was washed well withacetonitrile. The filtrate was concentrated to afford 10.7 g of an oilyresidue, which was extracted with ethyl acetate. The ethyl acetateextract was washed with water, dried with MgSO₄ and concentrated toyield 8.0 g of a dark oil. The oil was purified by preparative HPLC(Waters Associates Prep LC/System 500, utilizing 2 silica gel columnsand 3% methanol/methylene chloride as eluent). Concentration ofappropriate fractions provided 4.6 g of a red oil, which solidified uponstanding. A 3.4 g sample was taken up in ethyl acetate (100 ml) andfumaric acid (0.95 g) was added. The mixture was stirred at a mildreflux for 1 hour and then at ambient for 1.5 hours. The resultant beigesolid was collected by filtration and dried to yield 4.0 g. The productwas recrystallized twice from ethanol to provide 2.7 g (27%) of1-[4-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propoxy]-3-methoxyphenyl]ethanonehemifumarate as a beige powder, m.p.=186-188° C.

ANALYSIS: Calculated for C₂₃ H₂₇ N₃ O₃ S.0.5C₄ H₄ O₄ : 62.09% C 6.06% H8.69% N; Found: 62.01% C 6.06% H 8.68% N

EXAMPLE 381-[3,5-Dibromo-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-phenyl]ethanone

A stirred mixture of 6-fluoro-3(4-piperidinyl)-1,2-benzisoxazole (2.0 g,9.0 mmol), K₂ CO₃ (1.3 g), and1-[4-(3-bromopropoxy)-3,5dibromophenyl]ethanone (2.65 g, 9.0 mmol) andacetonitrile (50 ml) was heated at reflux for 3 hours. At the end of thereaction, the solvent was evaporated and the residue was extracted intodichloromethane (150 ml). The insolubles were filtered off. Thedichloromethane solution was concentrated down to an oil. Thepurification was done by flash chromatography on a silica gel column(SiO₂, 47 g; eluted with dichloromethane, 300 ml; 1% methanol indichloromethane, 600 ml). The material thus purified as a colorless oil,solidified on standing. Recrystallization from ethanol gave1-[3,5-dibromo-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl]phenyl]ethanoneas white crystals (2.93 g, 57%), m.p.=102-103° C.

ANALYSIS: Calculated for C₂₃ H₂₃ Br₂ FN₂ O₃ : 49.84% C 4.18% H 5.05% N;Found: 49.91% C 4.11% H 4.98% N

EXAMPLE 391-[4-[2-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxyphenyl]-ethanone

A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol),1-[4-(2-chloroethoxy)-3-methoxyphenyl]-ethanone (4.3 g, 20.0 mmol), K₂CO₃ (3.0 g, 21.8 mmol), acetonitrile (125 ml) and a catalytic amount ofKI was heated to reflux and stirred under nitrogen for 24 hours. At thispoint, an additional amount of K₂ CO₃ (1.0 g, 7.2 mmol) and alkylatingagent (0.4 g, 1.7 mmol) was added to the reaction mixture and heating atreflux was resumed for 24 hours. The reaction was cooled to ambienttemperature and filtered. The filter cake was washed with acetonitrileand the filtrate was concentrated to afford a dark oil. The oil wasextracted with methylene chloride, and the organic extract was washedwith water, dried with MgSO₄ and concentrated to yield 9.2 g of an oil.Purification by preparative HPLC (Waters Associates Prep LC/System 500utilizing 2 silica gel columns and 3% methanol/methylene chloride aseluent) provided 3.8 g of a soft, beige gum, which readily solidified.The compound was recrystallized twice from ethanol to give 2.1 g (28%)of1-[4-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethoxyl-3-methoxyphenyl]ethanoneas a beige solid, m.p.=98-100° C.

ANALYSIS: Calculated for C₂₂ H₂₅ N₃ O₃ S: 64.21% C 6.12% H 10.21% N;Found: 64.05% C 6.09% H 10.12% N

EXAMPLE 406-Fluoro-3-[1-(3-phenoxypropyl)-4-piperidinyl]-1,2-benzisoxazole

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.0 g, 18.2mmol), K₂ CO₃ (3.0 g, 21.8 mmol), KI (100 mg), 3-chloropropoxybenzene(3.4 g, 20.0 mmol), and acetonitrile was stirred at reflux undernitrogen for 30 hours. The reaction was poured into water and theaqueous mixture was extracted with ethyl acetate. The ethyl acetateextract was washed with brine, dried with MgSO₄ and concentrated toafford 6.2 g of a damp, beige solid. The compound was recrystallizedtwice from ethanol to yield (47%) of6-fluoro-3-[1-(3-phenoxypropyl)-4-piperidinyl]-1,2-benzisoxazole as alight beige solid, m.p.=78-80° C.

ANALYSIS: Calculated for C₂₁ H₂₃ FN₂ O₂ : 71.17% C 6.54% H 7.90% N;Found: 71.00% C 6.52% H 7.81% N

EXAMPLE 411-[4-[2-[4-(6-Chloro-1H-indazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxyphenyl]-ethanone

A mixture of 6-chloro-[3-(1-piperazinyl)]-1H-indazole (2.1 g, 8.9 mmol),K₂ CO₃ (1.5 g, 10.7 mmol), KI (100 mg),1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (2.2 g, 9.8 mml) andacetonitrile (70 ml) was stirred at reflux for 48 hours under N₂ Thecooled reaction was poured into water and the aqueous mixture wasextracted with ethyl acetate. The organic extract was washed with water,dried with MgSO₄ and concentrated to yield 6.0 of a light yellow oil.The oil was purified by preparative HPLC (Waters Associates prepLC/System 500, employing 2 silica gel columns and 5.5%methanol/methylene chloride as eluent). Concentration of later fractionsprovided 1.6 g of an off-white solid. This was combined with anadditional sample (3.4 g total) and two consecutive recrystallizationsfrom ethanol yielded 2.1 g (23%) of1-[4-[2-[4-(6-chloro-1H-indazol-3yl)-1-piperazinyl]ethoxy]-3-methoxyphenyl]ethanone as an off-white solid, m.p.=154-156° C.

ANALYSIS: Calculated for C₂₂ H₂₅ ClN₄ O₃ : 61.61% C 5.88% H 13.06% N;Found: 61.66% C 5.87% H 13.06% N

EXAMPLE 421-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]-2,2,2-trifluoroethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.5 g, 6.7mmol), 1-[4-(3-chloropropoxy)-3methoxyphenyl]-2,2,2-trifluoroethanone(2.0 g, 6.7 mmol), K₂ CO₃ (0.88 g), KI (0.1 g) and acetonitrile (50 ml)was stirred and refluxed for 16 hours. After cooling, the reaction waspoured into water and the aqueous mixture extracted with ethyl acetate.The extract was washed (H₂ O), dried (MgSO₄), and the solvent wasconcentrated to an oil, which upon evacuation at high vacuum afforded3.2 g of a waxy solid. The solid was chromatographed on a Waterspreparative LC (silica columns, eluting with 3%methanol-dichloromethane). Concentration of the appropriate fractionsgave 1.8 g (56%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]-2,2,2-trifluoro-ethanonesolid, m.p.=94-96° C.

ANALYSIS: Calculated for C₂₄ H₂₄ F₄ N₂ O₄ : 60.00% C 5.03% H 5.83% N;Found: 60.01% C 5.06% H 5.68% N

EXAMPLE 431-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl]-1-piperidinyl]propoxy]-3-methyl-mercaptophenyl]ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.88g, 8.5 mmol), K₂ CO₃ (1.8 g) and1-[4-(3-bromopropoxy)-3-methylmercaptophenyl]ethanone (2.3 g, 7.6 mmol)in acetonitrile (100 nil) was heated at reflux for 4 hours. At the endof the reaction, the solvent was concentrated, then diluted withdichloromethane (250 ml). The insolubles were filtered off. Thedichloromethane solution was concentrated to dryness as an oil.Purification was effected by flash chromatography on a silica gel column(SiO₂, 54 g, eluted with dichloromethane, 500 ml; 1%methanol-dichloromethane, 1.1 l). The purest fractions were combined togive a colorless oil which solidified to an off-white solid (2.4 g).Recrystallization from ethanol (100 ml) yielded1-[4-[3-[4-(6-fluoro-1,2-benzoisoxazol-3-yl]-1-piperidinyl]propoxy]-3-methylmercaptophenyl]ethanoneas off-white needle crystals, 2.15 g, m.p.=150-152° C.

ANALYSIS: Calculated for C₂₄ H₂₇ FN₂ O₃ S: 65.14% C 6.15% H 6.33% N;Found: 65.09% C 6.10% H 6.25% N

EXAMPLE 44 1-[4-(3-Bromopropoxy)-3-bromophenyl]ethanone

A stirred mixture of 3-bromo-4-hydroxyacetophenone (4.5 g, 21.2 mmol),K₂ CO₃ (4 g) and 1,3-dibromopropane (7.6 g) in acetonitrile (200 ml) washeated at reflux for 2 hours. At the end of the reaction, the solventwas removed and the residue was dissolved in dichloromethane (400 ml)and filtered. The dichloromethane solution was concentrated to an oil.The oil was added to isopropyl ether and stirred to causecrystallization (4.1 g; 58%). The solid was recrystallized fromisopropyl ether to give 3.5 g of1-[4(3-bromopropoxy)-3-bromophenyl]ethanone as glistening crystals,m.p.=83-84° C.

ANALYSIS: Calculated for C₁₁ H₁₂ Br₂ O₂ : 39.31% C 3.60% H; Found:39.80% C 3.55% H

EXAMPLE 45 1-[4-(3-Bromopropoxy)-3,5-dibromophenyl]ethanone

A stirred mixture of 3,5-dibromo-4-hydroxyacetophenone (3.0 g, 10.1mmol), K₂ CO₃ (2.8 g, 20.3 mmol), 1,3-dibromo-propane (4.0 g, 19.8 mmol)in acetonitrile (100 ml) was heated at reflux for 5 hours. The solventwas removed. The crude product was extracted into dichloromethane (150ml) and the insoluble inorganics were filtered off. The solution wasconcentrated to dryness again. Purification was carried out by flashchromatography on silica gel (45 g, SiO₂ ; eluted with 1:1hexane:dichloromethane). The material thus obtained (2.8 g) wasrecrystallized twice from isopropyl ether to give analytically pure1-[4-(3-bromopropoxy)-3,5-dibromophenyl]ethanone, m.p.=87-88° C.

ANALYSIS Calculated for C₁₁ H₁₁ Br₃ O₂ : 31.84% C 2.67% H; Found: 31.97%C 2.63% H

EXAMPLE 461-[4-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperidinyl]butoxyl-3-methoxyphenyl]-ethanone

A stirred mixture of 3-(4-piperidinyl)-1,2-benzisothiazole (2.6 g, 11.9mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (3.9 g, 13.1 mmol),K₂ CO₃ (2.0 g, 14.3 mmol), KI (200 mg) and acetonitrile (125 ml) wasstirred at reflux under nitrogen for 18 hours. The reaction was cooledto ambient temperature and filtered. The filter cake was washed wellwith fresh acetonitrile and the filtrate was concentrated to yield awet, brown solid. The residue was diluted with water and the aqueoussuspension was extracted with methylene chloride. The organic extractwas washed with water, dried with MgSO₄ and concentrated to afford 6.5 gof a dark oil. The oil was purified by preparative HPLC (WatersAssociates prep LC/System 500, utilizing 2 silica gel columns and 5%methanol/methylene chloride) to give 4.5 g of a beige solid. A 3.1 g 7.1mmol) sample was taken up in absolute ethanol (80 ml) and oxalic acid(0.67 g, 7.4 mmol) was added. The solution was refluxed mildly on asteam bath for 45 minutes and was then stirred at ambient temperaturefor 1 hour. The resultant suspension was diluted with anhydrous ether(150 ml) and stirred for 5 minutes. The solid was collected and dried toafford 3.1 g of a light, beige solid. The salt was recrystallized fromethanol to yield 2.8 g. The compound was converted back to the free basewith 50% NaOH to give 2.4 g, which was immediately recrystallized fromethanol to provide 1.5 g (29%) of1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanoneas a beige powder, m.p.=78-80° C.

ANALYSIS: Calculated for C₂₅ H₃₀ N₂ O₃ S: 68.46% C 6.91% H 6.39% N;Found: 68.34% C 6.85% H 6.33% N

EXAMPLE 471-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-phenylmethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10mmol), K₂ CO₃ (2.3 g) and1-[4-(3-bromopropoxy)-3-methoxyphenyl]phenylmethanone (3.47 g, 10 mmol)in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end ofreaction, the acetonitrile was concentrated and the mixture wasextracted into dichloromethane (200 ml). The insolubles were filteredoff and the solvent was evaporated to an oil. Purification was carriedout by flash chromatography over a silica gel column (SiO₂, 50 g; elutedwith dichloromethane, 600 ml; 1% methanol:dichloromethane, 600 ml; 2%methanol: 98% dichloromethane, 600 ml). The fractions containing thepure product were combined and concentrated to give 4.24 g (87%) of anoff-white solid. Recrystallization from ethanol (75 ml) gave 3.9 g of1-[4-[3-[4-(6-fluoro-1,2-benziosoxazol-3yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]phenylmethanoneas off-white crystals, m.p.=128-130° C.

ANALYSIS: Calculated for C₂₉ H₂₉ FN₂ O₄ : 71.30% C 5.98% H 5.73% N;Found: 71.31% C 5.99% H 5.75% N

EXAMPLE 481-[4-[3-[4-(6-Fluoro-1,2-benziosoxazol-3-yl)-1-piperidinyl]propoxy]-3-bromophenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.1 g, 9.5mmol), K₂ CO₃ (2.0 g) 1-[3-bromo-4-(3-bromopropoxy)phenyl]ethanone (3.1g, 9.2 mmol acetonitrile (100 ml) was heated at reflux for 3 hours. Atthe end of reaction, the solvent was concentrated and the mixture wasextracted into dichloromethane (200 ml). The insolubles were filteredoff. The dichloromethane was concentrated again. The crude residue waspurified by flash chromatography over a silica gel column (SiO₂, 49 g;eluted with dichloromethane, 500 ml; 1% methanol:dichloromethane, 600ml; 3% methanol: 97% dichloromethane, 600 ml). The material thusobtained (3.26 g, 72%) was recrystallized from ethanol (40 ml) to give1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-bromophenyl]ethanoneas light yellow crystals (3.0 g), m.p.=126-128° C.

ANALYSIS: Calculated for C₂₃ H₂₄ BrFN₂ O₃ : 58.12% C 5.09% H 5.89% N;Found: 57.64% C 5.35% H 5.55% N

EXAMPLE 493-[1-[3-[4-(1-Ethoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolehydrochloride

To a mixture of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3methoxy-.alpha.-methylbenzenemethanol(3.8 g, 89 mmol) in pyridine (25 ml) was added acetic anhydride (5 ml).The mixture was warmed briefly on the steam bath to effect solution, andthen the reaction was allowed to stand at ambient temperature for 16hours. Most of the pyridine was evaporated under reduced pressure andthe resultant oil was diluted with water. The aqueous solution was madebasic with dilute NaOH, and subsequently extracted with ethyl acetate.The organic extract was washed (water), dried (MgSO₄), and the solventconcentrated to give 3.7 g of the O-acetyl derivative as a colorlessoil. The compound was dissolved in diethyl ether and ethereal HCl wasadded to precipitate a gum-like hydrochloride salt, which upon treatmentwith refluxing ethyl acetate afforded 3.4 g of a crystalline salt,m.p.=143-145° C. Attempting to recrystallize the salt fromethanol:diethyl ether resulted in displacement of the acetate to affordthe ethyl ether. The salt of this product (2.8 g) was recrystallizedfrom ethanol:diethyl ether to yield 2.1 g (48%) of3-[1-[3-[4-(1-ethoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolehydrochloride, m.p.=139-141° C.

ANALYSIS Calculated for C₂₆ H₃₃ FN₂ O₄.HCl: 63.34% C 6.95% H 5.68% N;Found: 63.06% C 6.80% H 5.63% N

EXAMPLE 503-[1-[3-[4-(1-Acetoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolefumarate

A mixture of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-methoxy-α-methylbenzenemethanol(4.8 g, 11 mmol) in pyridine (45 ml) was warmed briefly to effectsolution and then acetic anhydride (6.3 ml) was added. The reactionstood at ambient temperature for 16 hours, was concentrated in vacuo,and the colorless oil that remained was dissolved in water. The aqueoussolution was made basic with saturated K₂ CO₃ solution, and the mixturewas extracted with diethyl ether. The extract was washed (water), dried(MgSO₄) and concentrated to afford 5.2 g of a thick, colorless oil. Theoil (4.8 g) was dissolved in anhydrous diethyl ether and fumaric acid(1.2 g, 0.01 mol) was added. The mixture was stirred at ambienttemperature for 4 hours, and then was permitted to stand at ambienttemperature for 16 hours. The resultant white,3-[1-[3-[4-(1-acetoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolefumarate was collected and afforded 3.0 g of material. The filtrate wastreated with an additional amount of fumaric acid (0.3 g) and 0.9 g moreof3-[1-[3-[4-(1-acetoxyethyl)-2-methoxyphenoxy]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolefumarate was harvested. The two batches were combined and recrystallizedfrom acetonitrile (twice) to yield 2.3 g (43%) of the acetate,m.p.=150-152° C.

ANALYSIS: Calculated for C₂₆ H₃₁ FN₂ O₃.C₄ H₄ O₄ : 61.43% C 6.01% H4.78% N; Found: 61.06% C 5.87% H 4.73% N

EXAMPLE 511-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]pentanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10mmol), K₂ CO₃ (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]pentanone(3.7 g, 11.3 mmol) in acetonitrile (140 ml) was heated at reflux for 4hours. At the end of the reaction, the mixture was cooled and filtered.The filtrate was concentrated to an oil. Purification was performed byflash chromatography over a silica gel column (SiO₂, 55 g; eluted with1% methanol in dichloromethane, 600 ml; 3% methanol: 97%dichloromethane, 400 ml). The fractions containing pure product werepooled and concentrated to a solid (4.3 g, 91%). Recrystallization fromethanol (10 ml) gave a powdery solid of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]pentanone(3.22 g), m.p.=79-80° C.

ANALYSIS: Calculated for C₂₇ H₃₃ FN₂ O₄ : 69.21% C 7.10% H 5.98% N;Found: 69.00% C 6.94% H 6.39% N

EXAMPLE 522-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-N-methyl-benzenaminehemifumarate

A mixture of 6-fluoro-3-(4-piperdinyl)-1,2-benzisoxazole (2.5 g, 11.4mmol), K₂ CO₃ (1.8 g, 13.0 mmol),4-(3-chloropropoxy)-2-methylaminobenzene (2.4 g, 12.0 mmol) andacetonitrile (100 ml) was stirred at reflux for 18 hours. The reactionwas cooled to ambient temperature and was poured into water. The aqueousmixture was extracted with ethyl acetate and the ethyl acetate extractwas washed with water, dried with MgSO4, and concentrated to yield 4.1 gof a brown oil. The oil was purified by preparative HPLC (WatersAssociates prep LC/System 500, utilizing 2 silica gel columns andeluting with 4% methanol-methylene chloride). Concentration ofappropriate fractions yielded 2.45 g of a beige oil. The product wastaken up in ethyl acetate (50 ml) and fumaric acid (0.78 g) was added.The mixture was stirred at mild reflux for 45 minutes and then atambient temperature for 1.5 hours. The product was isolated by vacuumfiltration to provide 2.5 g of a pale yellow solid. Recrystallizationfrom ethanol afforded 2.0 g (40%) of2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-N-methylbenzenamine hemifumarate as beige crystals, m.p.=180-182° C.

ANALYSIS: Calculated for C₂₂ H₂₆ FN₃ O₂.0.5C₄ H₄ O₄ : 65.28% C 6.40% H9.52% N; Found: 65.08% C 6.35% H 9.45% N

EXAMPLE 531-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]propanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8 g, 15.2mmol), K₂ CO₃ (3 g), 1-[4-(3bromopropoxy)-3-methoxyphenyl]propanone (4.6g, 18.2 mmol) in acetonitrile (100 ml) was heated at reflux for 2 hours.At the end of the reaction, the mixture was filtered and the solvent wasconcentrated and the residue was extracted into dichloromethane (300ml). The dichloromethane was filtered and concentrated again. The crudematerial (6.4 g) was purified by flash chromatography over a silica gelcolumn (SiO₂, 50 g; eluted with dichloromethane, 700 ml; 1% methanol indichloromethane, 1.4 l). The material thus purified (weight: 2.87 g,51%) was recrystallized from ethanol (25 ml) to give 2.13 g of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]propanoneas beige colored crystals, m.p.=118-119° C.

ANALYSIS: Calculated for C₂₅ H₂₉ FN₂ O₄ : 68.16% C 6.64% H 6.36% N;Found: 68.32% C 6.63% H 6.29% N

EXAMPLE 544-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10.0mmol), K₂ CO₃ (2.0 g) and 4-(3-bromopropoxy)-3-methoxybenzamide (2.32 g,8.0 mmol) in acetonitrile (80 ml) was heated at reflux for 5 hours. Atthe end of the reaction the solvent was evaporated. The residue wasextracted into dichloromethane. The inorganic insolubles were filteredoff. The dichloromethane was concentrated again. The crude residue waspurified by flash chromatography over a silica gel column (55 g, SiO₂ ;eluted with 1% methanol in dichloromethane, 1l; 2% methanol indichloromethane, 1 l). The material thus obtained weighed 2.93 g (84%)as white crystals. Recrystallization from hot ethanol (60 ml) gave 2.2 gof4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamideas white crystals, m.p.=163-164° C.

ANALYSIS: Calculated for C₂₃ H₂₆ FN₃ O₄ : 64.62% C 6.13% H 9.83% N;Found: 64.20% C 6.06% H 9.71% N

EXAMPLE 551-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-(methylamino)-phenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.3 g, 10.3mmol), K₂ CO₃ (1.4 g, 10.3 mmol),1-[4(3-chloropropoxy)-3-(methylamino)phenyl]ethanone (2.5 g, 10.3 mmol),KI (0.10 g), and acetonitrile (100 ml) was stirred at reflux undernitrogen for 23 hours. The reaction was cooled to ambient temperature,poured into water, and the aqueous mixture was extracted with ethylacetate. The ethyl acetate extract was washed twice with water, driedwith MgSO₄ and was concentrated to yield 4.8 g of a damp, brown solid.The compound was isolated by preparative HPLC (Waters Associates prepLC/System 500, utilizing 2 silica gel columns and 4% methanol-methylenechloride as eluent). Concentration of appropriate fractions afforded 2.4g. Recrystallization from ethanol gave 2.1 g of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-(methylamino)phenyl]ethanoneas a beige solid, m.p.=151-153° C.

ANALYSIS: Calculated for C₂₄ H₂₈ FN₃ O₃ : 67.75% C 6.63% H 9.88% N;Found: 67.83% C 6.76% H 9.90% N

EXAMPLE 561-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-ethoxyphenyl]-ethanone

A suspension of NaH (0.28 g of a 50% oil dispersion, 5.9 mmol) indimethylformamide (20 ml) was cooled to 4° C. in an ice bath. To thiswas added, dropwise,1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone(2.3 g, 0.0056 mol) dissolved in dimethylformamide (40 ml). After totaladdition, the mixture was stirred under nitrogen for 1 hour. keeping thetemperature below 10° C. A solution of bromoethane (1.3 g, 11.8 mmol)dissolved in dimethylformamide (15 ml) was then added, dropwise, to thereaction mixture. Stirring under nitrogen was continued for 3 hoursallowing the temperature to slowly rise to ambient temperature. Thereaction was cooled in an ice bath, water was added and the aqueousmixture was extracted with ethyl acetate. The ethyl acetate extract waswashed with water, dried with MgSO₄, and was concentrated to yield 3.9 gof a damp, beige solid. The solid was triturated with diethyl ether andfiltered to yield 1.5 g. This was combined with an additional sample(3.5 g total), and recrystallization from ethanol provided 3.0 g (57%)of glistening, beige crystals of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-ethoxyphenyl]ethanone,m.p.=112-114° C.

ANALYSIS: Calculated for C₂₅ H₂₉ FN₂ O₄ : 68.16% C 6.64% H 6.36% N;Found: 68.10% C 7.03% H 6.35% N

EXAMPLE 57 1-[4-(3-Bromopropoxy)-3-(methylmercapto)phenyl]ethanone

A mixture of 1-[4-hydroxy-3-(methylmercapto)phenyl]-ethanone (5.4 g; 30mmol), K₂ CO₃ (4.2 g), 1,3-dibromopropane (8 g, 39 mmol) in acetonitrile(150 ml) was heated at reflux for 3 hours and stirred at roomtemperature overnight. Acetonitrile was removed at reduced pressure andthe residue was extracted into dichloromethane (250 ml). Insolubles werefiltered off. The dichloromethane solution was concentrated. The crudeproduct was purified on a silica gel column (SiO₂, 100 g; eluted with3:2 hexane:dichloromethane, 1.6 l). The compound crystallized uponconcentration, and the product (3.5 g, 39%) was recrystallized fromethanol (40 ml) to yield1-[4-(3-bromopropoxy)-3-(methylmercapto)phenyl]ethanone as whiteneedles, 2.0 g, m.p.=120-122° C.

ANALYSIS: Calculated for C₁₂ H₁₅ BrO₂ S: 47.53% C 4.99% H; Found: 47.74%C 4.91% H

EXAMPLE 58 4-(3-Bromopropoxy)-3-methoxybenzonitrile

A mixture of 4-hydroxy-3-methoxybenzonitrile (7.5 g, 50 mmol), K₂ CO₃(12.5 g), and 1,3-dibromopropane (15 g, 75 mmol) in acetonitrile (100ml) was heated at reflux for 3 hours and left standing at roomtemperature overnight. The solvent of the reaction was removed on arotary evaporator, and the crude solid was extracted into methylenechloride (500 ml). The insolubles were filtered off. The dichloromethanesolution was concentrated and the material was purified on a flashchromatography column (SiO₂, 105 g; eluted with 2:3dichloromethane:hexane, and then with dichloromethane). The desiredproduct thus purified weighed 7.74 g (52%). Recrystallization twice fromethanol gave analytically pure 4(3-bromopropoxy)-3-methoxybenzonitrile,m.p.=99-101° C.

ANALYSIS: Calculated for C₁₁ H₁₂ BrNO₂ : 48.91% C 4.48% H 5.19% N;Found: 49.49% C 4.47% H 5.21% N

EXAMPLE 59 1-[4-(3-Bromopropoxy)-3-methylphenyl]ethanone

A mixture of 4-hydroxy-3-methylacetophenone (14.5 g, 96 mmol), K₂ CO₃(17.5 g, 144 mmol), and 1,3-dibromopropane (30 g, 144 mmol) inacetonitrile (400 ml) was heated at reflux for 6 hours. At the end ofthe reaction, the solvent was removed on a rotary evaporator, and thecrude solid was extracted into dichloromethane (750 ml). The insolubleinorganics were filtered off. The dichloromethane solution wasconcentrated again to a crude oil (34.5 g). Purification was effected byflash chromatography over a silica gel column (SiO₂, 150 g; eluted with7:3 hexane:dichloromethane, 2 l; and dichloromethane 2 l). The materialthus purified weighed 14.6 g (56%) and was recrystallized from ethanol.Recrystallization again from ethanol gave analytically pure1-[4-(3-bromopropoxy)-3-methylphenyl]ethanone, m.p.=59-61° C.

ANALYSIS: Calculated for C₁₂ H₁₅ BrO₂ : 53.15% C 5.58% H; Found: 53.35%C 5.52% H

EXAMPLE 60 1-[4-(3-Bromopropoxy)-3-methoxyphenyl]phenylmethanone

A mixture of 1-(4hydroxy-3-methoxyphenyl)phenyl-methanone (14 g, 61.4mmol), K₂ CO₃ (13 g, 92.1 mmol), and 1,3-dibromopropane (28 g, 86 mmol)in acetonitrile (400 ml) was heated at reflux for 4 hours. The reactionwas followed by thin layer chromatography. At the end of the reaction,the inorganics were filtered off and the solvent was removed on a rotaryevaporator. The residue was purified on a flash chromatographic column(SiO₂, 140 g, eluted with 4:1 hexane:dichloromethane, 1.2 1) to give apartially solidified material: 15.44 g (72%). Recrystallization twicefrom ethanol gave 2.84 g of1-[4-(3-bromopropoxy)-3-methoxyphenyl]phenylmethanone as white crystals,m.p.=88-89° C.

ANALYSIS: Calculated for C₁₇ H₁₇ BrO₃ : 58.47% C 4.91% H; Found: 59.03%C 4.87% H

EXAMPLE 61N-[2-[3-[4-(6-fluoro1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide

(A) N-[2-(3-phenylsulfonyloxypropoxy)phenyl]acetamide

To a solution of N-[2-(3-hydroxypropoxy)phenyl]-acetamide (Example 113)(7.5 g, 36 mmol) in pyridine (90 ml), cooled to 0° C., was addedp-toluenesulfonyl chloride (13.6 g, 56 mmol). After the tosyl chloridewent into solution, the reaction was then allowed to stand at 5° C. for16 hours. The reaction was poured onto ice, and a brown oil settled. Theaqueous supernatant was decanted from the oil, and the residual oiltaken up in diethyl ether. The diethyl ether was washed with cold (5°C.) 3N HCl and then with brine. The organic layer was dried (MgSO₄), andconcentrated to afford a thick, brown oil, 5.3 g.

(B)N-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-phenyl]acetamide

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.4 g, 16mmol), N-[2-(3-phenylsulfonyloxypropoxy)phenyl]acetamide (5.3 g, 16mmol), K₂ CO₃ (2.2 g), and acetonitrile (50 ml) was stirred and refluxedfor 5 hours. The reaction was poured into water, and the aqueoussuspension was extracted with ethyl acetate. The ethyl acetate waswashed (water and brine), dried (MgSO₄), and the solvent wasconcentrated to afford 6.0 g of a thick, brown oil. The oil waschromatographed on a Waters Prep 500 LC on silica gel. Concentration ofthe appropriate fractions afforded 3.0 g of a beige solid. This wasrecrystallized from ethyl acetate to yield (with concentration of themother liquors) 2.2 g (33%) ofN-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamideas a beige solid, m.p.=118-120° C.

ANALYSIS: Calculated for C₂₃ H₂₆ FN₃ O₃ : 67.14% C 6.37% H 10.21% N;Found: 67.06% C 6.43% H 10.23% N

EXAMPLE 621-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-dimethyl-aminophenyl]ethanone

(A) 1-[4-(3-Chloropropoxy)-3-dimethylaminophenyl]ethanone

To a suspension of sodium hydride (2.3 g, 48.5 mmol of 50% oildispersion) with dimethylformamide (75 ml), and cooled to 3° C. in anice-salt bath and under a stream of nitrogen was added, dropwise,1-(4-hydroxy-3-dimethylaminophenyl)ethanone (8.7 g, 48.5 mmol) dissolvedin dimethylformamide (150 ml) so that the temperature did not go over 7°C. After the addition was over, the bath was removed and the reactionwas stirred at ambient temperature for 45 minutes. The ice bath wasreapplied and a solution of 1-bromo-3-chloropropane (8.4 g, 53.4 mmol)in dimethylformamide (25 ml) was added dropwise. After the addition wascomplete, the reaction was stirred for 18 hours at ambient temperatureunder nitrogen. The reaction was chilled to 7° C. in an ice bath andwater (200 ml) was carefully added. After stirring for 5 minutes, theaqueous mixture was extracted with ethyl acetate (5×200 ml). The ethylacetate extract was washed with water (2×50 ml), dried with MgSO₄, andconcentrated to yield 22.2 g of a black oily liquid. The compound waspurified by prep HPLC, and combination of appropriate fractions gave 5.0g of brown oil.

(B)1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-dimethylaminophenyl]ethanone

A mixture of 1-[4-(3-chloropropoxy)-3-dimethylaminophenyl]ethanone (2.9g, 11.3 mmol), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 11.3mmol), K₂ CO₃ (1.7 g, 12.2 mmol), KI (200 mg) and acetonitrile (125 ml)was stirred at reflux for 18 hours. The cooled reaction was poured intowater and the aqueous mixture was extracted with ethyl acetate. Theethyl acetate extract was washed with water, dried with magnesiumsulfate and concentrated to yield 5.3 g of an amber oil. The compoundwas purified by preparative HPLC (Waters Associates prep LC/System 500utilizing 2 silica gel columns) and concentration of appropriatefractions provided 1.65 g (33%). After combining with two additionalsamples, the compound (3.4 g, 7.74 mmol total) was taken up in ethylacetate and fumaric acid (0.90 g, 7.75 mmol) was added. The mixture wasstirred at a mild reflux for 30 minutes and then for 1 hour at ambienttemperature. The reaction was left to stand overnight and was thenfiltered to give 3.6 g. The compound was recrystallized twice fromethanol to provide 2.3 g and once from acetonitrile to yield 1.9 g ofthe compound as a fumarate salt. The compound was converted to the freebase by suspending it in dilute NaOH and extracting withdichloromethane. After washing the dichloromethane extract with waterand drying with MgSO₄, the solvent was removed in vacuo to give 1.4 g(14%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-dimethylaminophenyl]ethanoneas a beige solid, m.p.=94-96° C.

ANALYSIS: Calculated for C₂₅ H₃₀ FN₃ O₃ : 68.32% C 6.88% H 9.56% N;Found: 67.74% C 6.74% H 9.40% N

EXAMPLE 631-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-methoxyphenyl]ethanonehydrochloride

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.4 g, 20mmol), 1-[4-(3-chloropropoxy)-2-methoxyphenyl]ethanone (4.8 g, 20 mmol),K₂ CO₃ (2.8 g), KI (200 mg) and acetonitrile (110 ml) was stirred andrefluxed for 16 hours. The reaction was filtered and the filtrateconcentrated to afford 9.0 g of a brown oil. The oil was taken up inacetone and fumaric acid (2.5 g, 22 mmol) was added. The mixture washeated to reflux and then it was stirred at ambient temperature for 1hour. The resultant fumarate salt (7.0 g) was collected and thenreversed to the free base with aqueous sodium hydroxide to afford 4.6 gof a soft solid. The solid was flash chromatographed on silica gel withdichloromethane-methanol (10%) as eluent, and after concentration of theappropriate fractions afforded 3.6 g of an off-white solid. The solidwas dissolved in anhydrous ether and ethereal HCl was added toprecipitate 3.3 g of the hydrochloride salt. The salt was recrystallizedfrom ethanol to afford 3.3 g of product. Occluded alcohol was removed toyield 2.8 g (29%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]-2-methoxyphenyl]ethanonehydrochloride, m.p.=193-195° C.

ANALYSIS: Calculated for C₂₄ H₂₈ ClFN₂ O₄ : 62.27% C 6.10% H 6.05% N;Found: 61.88% C 5.90% H 5.96% N

EXAMPLE 641-[4-(3-Chloropropoxy)-3-methoxyphenyl]-2,2,2-trifluoroethanone

(A) 4-(3-Chloropropoxy)-3-methoxybenzoic acid

To a stirred suspension under nitrogen of sodium hydride (6.4 g, 130mmol, of about 50% oil dispersion-ether washed) in tetrahydrofuran (220ml) was added pyrazole (4.4 g, 60 mmol) in tetrahydrofuran (60 ml),dropwise. After complete addition, the reaction was stirred for about 15minutes, and then 4-(3-chloropropoxy)-3-methoxybenzaldehyde (24.5 g, 107mmol) was added. The nitrogen was stopped and air was sparged into thereactor for about 3 hours. The reaction was then allowed to stir atambient temperature open to the atmosphere for 16 hours. Water wasadded, the reaction was cooled in an ice bath, and concentratedhydrochloric acid (25 ml) was added dropwise. More water was added andthe yellow solid that separated was collected to afford 16.2 g ofproduct. The filtrate was then extracted with ethyl acetate to afford anadditional 9.3 g. The samples were combined and recrystallized fromacetonitrile to yield 12.6 g of a light, yellow solid, m.p.=154-156° C.A 4.0 g sample was recrystallized from acetonitrile to yield 2.6 g of ayellow solid. This was combined with 0.4 g from another sample andrecrystallized again from acetonitrile with charcoal treatment to afford2.0 g of 4-(3-chloropropoxy)-3-methoxybenzoic acid as a yellow solid,m.p.=157-159° C.

ANALYSIS: Calculated for C₁₁ H₁₃ ClO₄ : 54.00% C 5.35% H; Found: 54.65%C 5.34% H

(B) 4-(3-Chloropropoxy)-3-methoxybenzoyl chloride

To a mixture of 4-(3-chloropropoxy)-3-methoxybenzoic acid (2.4 g, 10mmol) in dichloromethane (5 ml) was added thionyl chloride (0.9 ml, 12mmol) dissolved in dichloromethane (5 ml). The reaction was stirred andrefluxed for 1 hour, and then the dichloromethane was removed in vacuoto leave a dark oil. The oil was triturated with hexane and the solidthat formed while scratching with a glass rod was collected to afford1.6 g of 4-(3-chloropropoxy)-3-methoxybenzoyl chloride, m.p.=60-63° C.

(C) 1-[4-(3-Chloropropoxy)-3-methoxyphenyl]-2,2,2-trifluoroethanone

To a stirred mixture of 4-(3-chloroproxy)-3-methoxybenzoyl chloride(10.0 g, 38 mmol) in methylene chloride (55 ml) cooled to -70° C., therewas condensed into a reactor bromotrifluoromethane (70 g, 47 mmol).There was then added to the reactor hexamethylphosphoroustriamide (9.4g, 41 mmol) dissolved in dichloromethane (7 ml). The first 90% was addedquite rapidly, and the remainder at a slower rate. After completeaddition, the reaction was stirred at -70° C. to -65° C. for anadditional hour. The reaction mixture was allowed to come to roomtemperature. An equal volume of hexane was added and the layers wereseparated. The lower layer was extracted with hexane and then withdiethylether. The extracts were combined and concentrated to yield 5.6 gof a thick, colorless oil. The oil was chromatographed on a Waters Prep500 LC utilizing two silica gel columns and eluting with 20% ethylacetate-hexane. Concentration of appropriate fractions gave 2.7 g of alight oil, which after evacuation at high vacuum solidified to a waxy,white solid (2.4 g) of1-[4-(3-chloropropoxy)-3-methoxyphenyl]-2,2,2-trifluoroethanone.

EXAMPLE 654-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-.beta.-methylbenzenemethanol

(A) 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone

A mixture of 1-[4-(3-chloropropoxy)-3-methoxy-phenyl]ethanone (10.0 g,41.2 mmol) and concentrated H₂ SO₄ (50 ml) was stirred at 65° C. for 23hours. The cooled reaction was poured into 250 g of ice and was stirredvigorously for 10 minutes. The aqueous mixture was extracted withdichloromethane (CH₂ Cl₂) and the resultant dichloromethane extract waswashed well with 5% sodium hydroxide. The basic phases were combined andwashed with dichloromethane. The aqueous mixture was cooled in an icebath and concentrated hydrochloric acid was added until a precipitateformed. The product was isolated by filtration and dried to yield 3.1 gof a light brown solid. This was combined with an additional sample (5.0g total) and two consecutive recrystallizations from toluene provided3.4 g (22%) of 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone as abeige solid, m.p.=101-103° C.

ANALYSIS: Calculated for C₁₁ H₁₃ ClO₃ : 57.78% C 5.73% H; Found: 58.17%C 5.66% H

(B) 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzene methanol

To a flask charged with sodium borohydride (1.5 g, 39.4 mmol) undernitrogen and chilled to 10° C. was added, slowly, a solution of1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone (6.0 g, 26.2 mmol)dissolved in ethanol-tetrahydrofuran (120 ml, 2:1). After totaladdition, the ice bath was removed and the reaction was stirred atambient temperature for 3 hours. An additional amount of sodiumborohydride (0.2 g, 5.3 mmol) was carefully added. After stirring atambient temperature for one hour, the solvent was removed in vacuo. Theresultant solid residue was diluted with water (100 ml) and leftovernight. The product was isolated by vacuum filtration yielding 3.8 g.Two consecutive recrystallizations from toluene provided 3.3 g (55%) of4-(3-chloropropoxy)-3-hydroxy-α-methylbenzene methanol as a light brownsolid, m.p.=107-109° C.

ANALYSIS: Calculated for C₁₁ H₁₅ ClO₃ : 57.27% C 6.55% H; Found: 57.60%C 6.43% H

(C)4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzenemethanol

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.3 g, 19.5mmol), 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzenemethanol (4.5 g,19.5 mmol), KI (200 mg), NaHCO₃ (1.8 g, 21.5 mmol) and CH₃ CN (125 ml)was stirred at reflux under nitrogen for 24 hours. The cooled reactionwas filtered and the filter cake was washed with CH₃ CN. The filtratewas concentrated to afford an oily residue, which was partitionedbetween water and ethyl acetate. The ethyl acetate extract was washedwith water, dried with MgSO₄, and concentrated to yield 8.6 g of a darkoil. The oil was purified by preparative HPLC (Waters Associates prepLC/system 500) to yield 5.0 g. The compound was recrystallized twicefrom ethanol to provide 3.9 g (49%) of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-hydroxy-α-methyl-benzenemethanol as a light beige solid, m.p.=142-144° C.

ANALYSIS: Calculated for C₂₃ H₂₇ FN₂ O₄ : 66.65% C 6.57% H 6.76% N;Found: 66.68% C 6.35% H 6.72% N

EXAMPLE 662-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]anilinedihydrochloride

(A) 2-(3-chloropropoxy)aniline

To a stirred suspension of sodium hydride (11.0 g, 230 mmol of a 50% oildispersion) in dimethylformamide (250 ml), under nitrogen, was added,dropwise, 2-aminophenol (25.0 g, 230 mmol) dissolved indimethylformamide (125 ml). After complete addition, the reaction wasstirred at ambient temperature for 1 hour, and then it was cooled to 5°C. (ice bath). 3-Chloro-1-bromopropane (36.2 g, 230 mmol) indimethylformamide (50 ml) was added, dropwise, so that the temperaturedid not go above 8° C. The reaction was stirred for 4 hours and thenpermitted to stand at ambient temperature for 16 hours. The reaction waspoured into water and extracted with ethyl acetate. The ethyl acetatewas washed (water), dried (MgSO₄), and the solvent concentrated toafford 25.4 g of a reddish, dark oil. About 12.0 g of the oil waschromatographed on HPLC columns. Concentration of the largest fractionsgave 5.4 g of 2-(3-chloropropoxy) aniline as an oil.

(B)2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]anilinedihydrochloride

A mixture of ⁶ -fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.8 g, 22mmol), 2-(3-chloropropoxy)aniline (4.0 g, 22 mmol), K₂ CO₃ (4.1 g, 22mmol), KI (0.2 g), acetonitrile (100 ml) was stirred and refluxed for 10hours. The reaction was poured into water and the aqueous mixture wasextracted with ethyl acetate. The extract was washed (water), dried(MgSO₄), and the solvent was concentrated to afford 9.0 g of a redsolid. The solid was triturated with diethyl ether to yield 3.0 g of abeige solid. This sample was combined with a sample (1.1 g) from anotherrun, and a hydrochloride salt was prepared by dissolving the free basein ethanol and then adding ethereal HCl. The resultant salt (3.5 g) wasrecrystallized twice from methanol-diethyl ether to afford 2.6 g (22%)of2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]anilinedihydrochloride as a brown solid, m.p.=253-255° C.

ANALYSIS: Calculated for C₂₁ H₂₄ FN₃ O₂.2HCl: 57.02% C 5.92% H 9.50% N;Found: 56.68% C 5.71% H 9.35% N

EXAMPLE 67N-[5-Acteyl-2-[3-[4-(6-fluoro1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]-acetamide

(A) Preparation of 1-[3-acetylamino-4-(3-chloropropoxy)phenyl]ethanone

A stirred mixture of 1-[3-acetylamino-4-hydroxyphenyl] ethanone (7.7 g,40 mmol), K₂ CO₃ (5.7 g), 3-chloro-1-bromopropane (8.9 g, 56 mmol) andacetone (100 ml) was refluxed for 16 hours. The reaction was allowed tocool to ambient temperature and filtered. Concentration of the filtrateyielded 8.5 g of a white solid. The solid was recrystallized fromtoluene and then from ethanol to afford 6.5 g of an off-white solid. A3.3 g sample of this material was flash chromatographed on silica gelwith ethyl acetate as eluent. Concentration of the appropriate fractionsafforded 2.8 g of a solid. The solid was recrystallized from toluene andthen from ethanol-water to yield 2.2 g (51%) of a solid, m.p.=124-126°C.

ANALYSIS: Calculated for C₁₃ H₁₆ ClNO₃ : 57.89% C 5.98% H 5.19% N;Found: 57.08% C 5.85% H 5.13% N

(B)N-[5-acetyl-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.4 g, 20mmol), 1-[3-acetylamino-4-(3-chloropropoxy)phenyl]ethanone (5.5 g, 20.5mmol), K₂ CO₃ (2.8 g), and acetonitrile (70 ml) was stirred and refluxedfor 16 hours. The reaction was poured into water and the aqueous mixturewas extracted with ethyl acetate. The extract was washed (water), dried(MgSO₄), and then it was concentrated to afford 9.5 g of a brown oil.The oil was taken up in ethyl acetate and ethereal HCl was added untilthe reaction was acidic. The crude, brown, hydrochloride salt wascollected (8.4 g), and was immediately converted to the free base withNH₄ OH, to afford 5.4 g of the compound as a brown oil. The oil waschromatographed on a Waters Preparative HPLC utilizing silica gelcolumns. Concentration of the appropriate fractions yielded 3.5 g ofN-[5-acetyl-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-phenyl]acetamideas a white solid, m.p.=108-110° C.

ANALYSIS: Calculated for C₂₅ H₂₈ FN₃ O₄ : 66.21% C 6.22% H 9.27% N;Found: 66.12% C 6.25% H 9.27% N

EXAMPLE 683-[1-[3-(4-Ethyl-3-methoxyphenoxy)propyl]-4-piperidinyl-6-fluoro-1,2-benzisoxazolehydrochloride

(A) 4-ethyl-2-methoxyphenol

Acetovanillone (Aldrich, 11.0 g, 66 mmol) was dissolved in absoluteethanol (200 ml) and added to 1.5 g of 5% palladium on carbon. A fewdrops of concentrated hydrochloric acid were added and the mixturehydrogenated on a shaker at 42 psi. The reaction mixture was filteredthrough Celite, and the filtrate was concentrated to afford 10.3 g of agolden liquid. This was diluted with water, extracted with diethyl etherand the organic phase was washed with water and sodium bicarbonate. Thesolvent was dried (MgSO₄) and concentrated to afford 9.3 g of a slightlyyellow liquid.

(B) 4-ethyl-2-methoxy4-(3-chloropropoxy)benzene

A mixture of 4-ethyl-2-methoxyphenol (9.0 g, 59 mmol),3chloro-1-bromopropane (13.0 g, 83 mmol), K₂ CO₃ (6.2 g) and acetone(200 ml) was stirred and refluxed for 16 hours. The reaction was allowedto cool, and then it was filtered. The filtrate was concentrated to aclear liquid. The liquid was diluted with dilute aqueous NaOH, and thebasic mixture was extracted with diethyl ether. The diethyl ether waswashed (water), dried (MgSO₄), and the solvent was concentrated toafford 11.9 g of a golden liquid. The liquid was flash chromatographed.This gave a colorless liquid, 9.9 g of4-ethyl-2-methoxy-4-(3-chloropropoxy)benzene.

(C)3-[1-[3-(4-ethyl-2-methoxyphenoxy)propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolehydrochloride

A stirred mixture of 6-fluoro-3(4-piperidinyl)-1,2-benzisoxazole (4.0 g,18 mmol), KI (0.4 g), K₂ CO₃ (2.5 g),4-ethyl-2-methoxy-4-(3-chloropropoxy)benzene (4.4 g, 18 mmol) andacetonitrile was refluxed for 8 hours. The reaction was poured intowater, and the aqueous suspension was extracted with ethyl acetate. Theethyl acetate extract was washed (water) dried (MgSO₄) and the solventconcentrated to afford 7.0 g of a brown oil. The oil was combined with2.0 g from another sample, and the combined sample was flashchromatographed on silica gel. Concentration of the appropriatefractions yielded 4.4 g of a thick oil, which solidified on standing.The solid was dissolved in ethyl acetate and ethereal HCl was added toprecipitate 4.5 g of a white hydrochloride salt. Recrystallization fromacetone afforded 3.0 g (29%) of3-[1-[3-(4-ethyl-2-methoxyphenoxy)-propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazolehydrochloride as a white solid, m.p.=150-152° C.

ANALYSIS: Calculated for C₂₄ H₂₉ FN₂ O₃.HCl: 64.21% C 6.74% H 6.24% N;Found: 64.38% C 6.84% H 6.14% N

EXAMPLE 691-[3,5-Dimethoxy-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-phenyl]ethanone

(A) 3,5-dimethoxy-4-(3-bromopropoxy)acetophenone

To 3,5-dimethoxy-4-hydroxyacetophenone (5.2 g) in dimethylformamide (50ml) at 0° C. under nitrogen, was added sodium hydride (700 mg, 1.1 eq,98%). The resulting mixture was stirred for ten minutes until evolutionof gas ceased. Potassium carbonate (4 g) was added, and then1,3-dibromopropane was added. The mixture was heated at 60° C. for onehour. When the reaction was complete, the mixture was poured into awater/ice mixture and the resulting solution was extracted with ethylacetate (600 ml). The ethyl acetate was washed with water, brine, andthen concentrated to an oil (9 g). The product was purified bychromatography on silica gel to yield3,5-dimethoxy-4-(3-bromopropoxy)acetophenone as a light oil, 7.6 g.

(B)1-[3,5-dimethoxy4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0.g, 13.6 mmol), K₂ CO₃ (2.1 g, 15 mmol), and3,5-dimethoxy-4-(3-bromopropoxy)acetophenone (4.4 g, 13.8 mmol) inacetonitrile (50 ml) was heated at reflux for 3 hours. At the end of thereaction, the mixture was diluted with dichloromethane 200 ml). Theinsolubles were filtered. The solution was concentrated to an oil (10g). The purification was done by flash chromatography on a silica gelcolumn. The product was obtained as a colorless oil (3.85 g, 61%), whichcrystallized from ethanol (400 ml) to give 2.94 g of1-[3,5-dimethoxy-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]phenyl]ethanoneas off-white crystals, m.p.=107-108° C.

ANALYSIS: Calculated for C₂₅ H₂₉ FN₂ O₅ : 65.78% C 6.40% H 6.14% N;Found: 65.84% C 6.44% H 6.15% N

EXAMPLE 70N-[3-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamidehemifumarate

(A) 3-(3-acetamidophenoxy)propyl bromide

To 3-acetamidophenol (15.1 g) in dichloromethane (500 ml, dry) was addedpotassium carbonate (20 g) and then 1,3-dibromopropane (30 g). Theresulting mixture was heated at reflux for 6 hours and then overnight atroom temperature. After an additional 24 hours, the reaction wascomplete. Solids were filtered from the reaction mixture, and thesolution was concentrated to an oil, which was purified to yield3-(3-acetamidophenoxy)propyl bromide, 13.2 g.

(B)N-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]phenyl]acetamidehemifumarate

A stirred mixture of 6fluoro-3-(4-piperidinyl)-1,2-benzisoxazole(9.25 g,42 mmol). K₂ CO₃ (8 g, 58 mmol) and 3-(3-acetamidophenoxy)propyl bromide(11.4 g, 42 mmol) in acetonitrile (350 ml) was heated at reflux for 3hours. At the end of the reaction, the reaction was cooled, filtered andthe solids washed with dichloromethane (100 ml). the organic solvent wasremoved on a rotary evaporator to leave a crude oil (18 g). Purificationwas by flash chromatography on a silica gel column. The product thuspurified was an oil, 12.2 g, 70%. Analytically pure sample was preparedby dissolving 3 g of free base in ethanol and treating with fumaric acidsolution in ethanol (850 mg:5 ml). TheN-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamidehemifumarate crystals obtained weighed 2.73 g, m.p.=184-186° C.Calculated for C₂₃ H₂₆ FN ₃ O₂.0.5C₄ H₄ O₄ : 63.95% C 6.01% H 8.94% N;Found: 63.47% C 5.94% H 8.78% N

EXAMPLE 713-[3-[4-(6Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]aniline

A stirred mixture ofN-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidiny]propoxyl]phenyl]acetamide(9.2 g, 22 mmol), prepared as described in the previous example, in 15%hydrochloric acid (110 ml) was heated at 100° C. for 2.5 hours until ahomogeneous solution resulted. The reaction was cooled to 0° C. in anice bath and basified with 50% NaOH. The product was extracted withethyl acetate (3×200 ml). The ethyl acetate solution was washed withwater, brine, then dried over Na₂ SO₄. The solvent was removed. Thecrude product was purified on a flash chromatography column. The productthus obtained was a solid: 6.6 g (80%). Recrystallization from hotethanol (50 ml) gave3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-anilineas off-white crystals: 3.46 g, m.p.=115-117° C.

ANALYSIS: Calculated for C₂₁ H₂₄ FN₃ O₂ : 68.27% C 6.55% H 11.37% N;Found: 68.34% C 6.53% H 11.31% N

EXAMPLE 723-[3-[4-(6Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyaniline

A mixture of3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenylacetamide(4.2 g, 9.5 mmol), prepared as in Example 26 above, in 15% hydrochloricacid (60 ml) was heated at reflux (110° C.) for 2 hours. At the end ofthe reaction, the solution was cooled to 0° C. then basified with 25%NaOH to pH of 10. The product was extracted into ethyl acetate (300 ml).The ethyl acetate solution was washed with water and brine, then driedover Na₂ SO₄. The solvent was removed at reduced pressure. The crude oilwas purified by flash chromatography on a silica gel column. The productthus purified was an oil, 2.6 g. Crystallization from ethanol (5 ml) andpetroleum ether (3 ml) yielded3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-4-methoxyanilineas fine crystals: 1.2 g; m.p.=94-95° C.

ANALYSIS: Calculated for C₂₂ H₂₆ FN₃ O₃ : 66.15% C 6.56% H 10.52% N;Found: 66.16% C 6.54% H 10.44% N

EXAMPLE 731-[4-[3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy-3-methylamino-phenyl]ethanonefumarate

(A) 1-[(3-N-acetyl-N-methylamino)4-hydroxyphenyl]ethanone

A solution of 2-methoxy(methylamino)benzene (26.0 g, 190 mmol) and1,2-dichloroethane was cooled to 10-15° C. and a solution of acetylchloride (33.8 g, 430 mmol) dissolved in dichloroethane (50 ml) wasdripped in slowly. Following this addition, an additional 100 mldichloroethane was added. The reaction was cooled to 0° C. and aluminumchloride (72.3 g, 540 mmol) was added over the course of 45 minutes sothat the temperature did not exceed 10° C. After complete addition, thereaction was heated to reflux and was stirred for 18 hours undernitrogen. The reaction was cooled and was poured into ice. The resultingaqueous phase was extracted further with dichloromethane and thecombined extracts were washed with H₂ O, dried with MgSO₄, andconcentrated to yield 32.0 g of1-[(3-N-acetyl-N-methyl-amino)-4-hydroxyphenyl]ethanone as a brownsolid, m.p.=168-171 ° C.

(B) 1-(4-hydroxy-3-methylaminophenyl)ethanone

A mixture of 1-[(3-N-acetyl-N-methylamino)-4-hydroxyphenyl]ethanone(15.0 g, 72.4 mmol) and concentrated HCl (150 ml) was stirred at refluxfor 3 hours. The heat was terminated and the reaction stood overnight.The reaction mixture was transferred to a 1 L beaker and was chilled inan ice-salt bath. Solid sodium bicarbonate was added cautiously untilthe pH was about 2, and the aqueous mixture was allowed to standovernight. The reaction mixture was continued to be made basic by theaddition of solid sodium bicarbonate. After pH 8 was achieved, thereaction mixture was extracted with ethyl acetate. The ethyl acetateextract was washed with a 200 ml aliquot of water and this was then fedthrough a bed of Celite. After washing the cake with fresh ethyl acetatethe phases were separated. The ethyl acetate extract was washed severalmore times with water, dried with MgSO₄ and concentrated to yield 10.5 gof a dark solid of 1-(4-hydroxy-3-methylaminophenyl)ethanone.

(C) 1-[4-(3-chloropropoxy)-3-methylaminophenyl]ethanone

To a stirred suspension of sodium hydride (0.87 g, 18.2 mmol of a 50%oil dispersion) in dimethylformamide (25 ml) under nitrogen and cooledto 0° in an ice-salt bath was added, dropwise, a solution of]-(4-hydroxy-3-methylamino-phenyl)ethanone (3.0 g, 18.2 mmol) dissolvedin dimethylformamide (55 ml) so that the temperature did not rise above3° C. After the addition was complete, the reaction was stirred for 80minutes at ambient temperature. The reaction was cooled to 5° C. and asolution of 1-bromo-3-chloropropane (3.1 g, 0.0120 mol) indimethylformamide (20 ml) was added dropwise. After this addition wascomplete, the ice bath was removed and the reaction was stirred atambient temperature for 2.5 hours. Water (75 ml) was carefully added andafter stirring vigorously for 5 minutes, the reaction was left to standovernight. The aqueous mixture was extracted with ethyl acetate and theethyl acetate extract was washed with water, dried with MgSO₄, andconcentrated to yield 3.9 g of a dark solid. The compound was purifiedby preparative HPLC to afford 2.4 g of a beige solid. This was combinedwith an additional sample (3.8 g total) and two consecutiverecrystallizations from ethanol gave 2.1 g (31%) of1-[4-(3-chloropropoxy)-3-methyl-aminophenyl]ethanone as a fluffy, beigesolid, m.p.=115-117° C.

ANALYSIS: Calculated for C₁₂ H₁₆ ClNO₂ : 59.63% C 6.67% H 5.79% N;Found: 59.49% C 6.64% H 5.79% N

(D)1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy-3-methylaminophenyl]ethanonefumarate

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (1.9g, 79 mmol), 1-[4-(3chloropropoxy)-3methylaminophenyl]ethanone (1.9 g,79 mmol), K₂ CO₃ (1.1 g), KI (0.1 g), and acetonitrile (95 ml) wasrefluxed for 16 hours. The reaction was poured into water and theaqueous suspension extracted with ethyl acetate. The extract was washed(water and brine), dried (MgSO₄), and then the solvent was concentratedto afford 3.2 g of a thick, brown oil. The oil was chromatographed on aWaters Prep 500 LC on silica gel columns, and concentration of theappropriate fractions afforded 1.5 g of a brown oil. The oil wasdissolved in acetone and fumaric acid (0.4 g, 0.003 mol) was added, and1.9 g of a white fumarate salt was collected. The salt wasrecrystallized from dimethylformamide to yield 1.1 g (25%) of1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy-3-methylaminophenyl]ethanonefumarate as a white solid, m.p.=198-200° C.

ANALYSIS: Calculated for C₂₈ H₃₂ FN₃ O₆ S: 60.31% C 5.78% H 7.54% N;Found: 60.02% C 5.88% H 7.68% N

EXAMPLE 74N-[3-[3-[4-(6Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-4-methoxy-phenyl]acetamide

(A) N-[3-(3-chloropropoxy)-4-methoxyphenyl]acetamide

To a stirred suspension, under nitrogen, of sodium hydride (1.8 g, 38mmol) in dimethylformamide (60 ml) was added dropwise,N-(3-hydroxy-4-methoxy)acetamide (6.1 g, 34 mmol) dissolved indimethylformamide (23 ml). After complete addition, the reaction wasstirred at ambient temperature for 0.5 hour, and then3-chloro-1-bromopropane (5.2 g, 33 mmol) in dimethylformamide (10 ml)was added, dropwise. The reaction was stirred at ambient temperature for16 hours, and then it was poured into water, and the aqueous mixture wasextracted with ethyl acetate. The extract was washed (water), dried(MgSO₄) and the solvent concentrated to afford a purple solid. The solidwas triturated with diethyl ether and collected to afford 2:8 g of apurple solid. This sample was combined with a sample (1.2 g) fromanother run and was recrystallized from toluene twice to yield 2.9 g ofan off-white solid. The solid was flash chromatographed on 200 g ofsilica gel, eluting the column with ethyl acetate, and subsequentconcentration of the appropriate fractions afforded 2.4 g of a whitesolid. Recrystallization of the compound from toluene yielded 2.2 g(17%) of N-[3-(3-chloropropoxy-4-methoxyphenyl]acetamide, m.p.=112-114°C.

ANALYSIS: Calculated for C₁₂ H₁₆ ClNO₃ : 55.93% C 6.26% H 5.44% N;Found: 56.25% C 6.29% H 5.44% N

(B)N-[3-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]acetamide

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.0g, 17 mmol), N-[3-(3-chloropropoxy)-4-methoxyphenyl]acetamide (4.3 g, 17mmol), K₂ CO₃ (2.3 g), KI (0.2 g) and acetonitrile (200 ml) was refluxedfor 10 hours. The cooled reaction mixture was filtered and the filtratewas concentrated to yield a dark oil. The oil was dissolved in acetone,and ethereal HCl was added to yield 5.7 g of a yellow hydrochloridesalt. The salt was reversed to the free base and the resultant oil (5.2g) was chromatographed on a Waters Associates Prep LC utilizing silicagel columns. Concentration of the appropriate fractions yielded 4.7 g ofan oil, which was converted to a hydrochloride salt. The salt wasconverted to its free base yielding 2.8 g of a brown oil. The oil wasstirred vigorously with ether to yield 1.4 g (18%) ofN-[3-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-4-methoxyphenyl]-acetamideas a white solid, 1.4 g, m.p.=109-111° C.

ANALYSIS: Calculated for C₂₄ H₂₈ FN₃ O₃ S: 63.00% C 6.17% H 9.18% N;Found: 62.80% C 6.17% H 8.86% N

EXAMPLE 751-[4-[3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanonehydrochloride

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.0g, 17 mmol), 1-[4-(3chloropropoxy)-3methoxyphenyl]ethanone (4.1 g, 17mmol), K₂ CO₃ (2.3 g), KI (0.2 g), and acetonitrile (100 ml) wasrefluxed for 9 hours. The reaction was poured into water, and theaqueous mixture was extracted with ethyl acetate. The extract was washed(water), dried (MgSO₄), and the solvent was concentrated to afford 8.0 gof a brown oil. The oil was chromatographed on a Waters Prep 500 HPLC onsilica gel columns. Concentration of the appropriate fractions affordeda gum-like residue, which upon trituration with isopropyl ether afforded1.9 g of a white solid. The solid was dissolved in absolute ethanol, andethereal HCl was added to precipitate 1.7 g of a hydrochloride salt.Concentration of the isopropyl ether filtrate, and similar treatment ofthe residue, afforded an additional 0.5 g of the salt. The samples werecombined and recrystallized from absolute ethanol to yield 1.7 g (21%)of1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanonehydrochloride as a white solid, m.p.=221-223° C.

ANALYSIS: Calculated for C₂₄ H₂₇ FN₂ O₃ S.HCl: 60.18% C 5.89% H 5.85% N;Found: 60.01% C 5.97% H 5.79% N

EXAMPLE 76N,N-Dimethyl-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxybenzamide

(A) N,N-dimethyl4-bromopropoxy-3-methoxybenzamide

To N,N-dimethyl-4-hydroxy-3-methoxybenzamide (5.64 g, 28.7 mmol) inacetonitrile (450 ml) was added potassium carbonate (7.9 g) followed by1,3dibromopropane (11.6 g). The resulting reaction mixture was refluxedfor 3 hours and stirred at room temperature for 12 hours. The mixturewas filtered and concentrated to an oil. Following purification bycolumn chromatography, N,N-dimethyl-4-bromopropoxy-3-methoxybenzamide asa colorless oil (7.6 g) was obtained.

(B)N,N-dimethyl-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxybenzamide

A stirred mixture of 6-fluoro-3(4-piperidinyl)-1,2-benzisoxazole (3.9 g,17.7 mmol), N,N-dimethyl-4-bromopropoxy-3-methoxybenzamide (5.54 g, 17.5mmol) and K₂ CO₃ (3 g) in acetonitrile (250 ml) was heated at reflux forone hour. At the end of the reaction, the insolubles were filtered andwashed with dichloromethane. The solvent was removed on a rotaryevaporator. The residue was purified by flash chromatography over asilica gel column. The product thus obtained as an oil weighed 7 g.Crystallization from hot ethanol (45 ml) afforded analytically pureN,N-dimethyl-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide,3.95 g, 50%, as light yellow crystals, m.p.=126-127° C.

ANALYSIS: Calculated for C₂₅ H₃₀ FN₃ O₄ : 65.92% C 6.64% H 9.22% N;Found: 65.76% C 6.64% H 9.14% N

EXAMPLE 77 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone oxime

A mixture of1-[4-[3-[4-(6fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone(4.3 g, 10 mmol), prepared as in Example 3 above, hydroxylaminehydrochloride (1.3 g, 18 mmol), ammonium acetate (1.7 g, 22 mmol) andethanol-H₂ O was stirred and refluxed for 16 hours. The reaction waspoured into water, and the mixture was cooled in an ice bath for 2hours. The resultant, white solid was collected, washed with water anddried to yield 4.6 g of hydrochloride salt of the oxime, m.p.=216-218°C. The compound was dispersed in water and ammonium hydroxide was addeduntil the suspension was decidedly basic. The basic suspension was thenextracted with dichloromethane, and after washing with water, drying(MgSO₄), and concentrating the extract, 3.0 g of white solid melting at168-170° C. were harvested. The compound was recrystallized fromdimethylformamide to yield 2.3 g (52%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanoneoxime as a white solid, m.p.=168-170° C.

ANALYSIS: Calculated for C₂₄ H₂₈ FN₃ O₄ : 65.29% C 6.39% H 9.52% N;Found: 65.27% C 6.44% H 9.46% N

EXAMPLE 781-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]methoxyphenyl]ethanoneoxime O-methyl ether

A solution of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]methoxyphenyl]ethanone(4.3 g, 10 mmol), prepared as in Example 3 above, methoxylaminehydrochloride (0.93 g, 10 mmol) in pyridine (75 ml)/ethanol (75 ml) wasrefluxed for 16 hours. Most of the solvent was evaporated under reducedpressure, and the residue was diluted with water to precipitate 1.6 g ofa white solid, m.p. 200-201° C. The aqueous filtrate upon standingdeposited another crop of white crystals, which yielded 1.2 g of a pale,yellow solid with a m.p. of 70-72° C. The initial crop of crystals wasconverted to its free base with aqueous NaOH. After extractive workupwith ethyl acetate, 1.2 g of the free base was obtained. The two sampleswere combined and recrystallized from isopropyl ether to afford 2.0 g(44%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]methoxyphenyl]ethanoneoxime O-methyl ether as colorless crystals, m.p.=97-99° C.

ANALYSIS: Calculated for C₂₅ H₃₀ FN₃ O₄ : 65.92% C 6.64% H 9.22% N;Found: 65.89% C 6.86% H 9.15% N

EXAMPLE 791-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanonehydrazone

A stirred mixture of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propopoxy]3-methoxyphenyl]ethanone (4.3 g, 10 mmol), prepared as in Example 3 above, hydrazine(0.8 g, 2.5 mmol), and ethanol (40 ml) was refluxed for 16 hours. Thecooled solution was concentrated to yield an oily residue. The residuewas triturated with water and the resultant solid was collected toafford 4.2 g of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanonehydrazone as a yellow solid. The compound was recrystallized fromisopropanol and then from toluene to afford 1.7 g (39%), m.p.=106-108°C.

ANALYSIS: Calculated for C₂₄ H₂₉ FN₄ O₃ : 65.44% C 6.64% H 12.72% N;Found: 65.38% C 6.55% H 12.55% N

EXAMPLE 806-Fluoro-3-[1-[3-[2-methoxy-4-(1-methylethenyl)phenoxy]propyl]-4-piperidinyl]-1,2-benzisoxazolehydrochloride

A solution of butyllithium (4.7 ml of a 2.3M solution in hexanes, 10.7mmol) in tetrahydrofuran (65 ml) was stirred under nitrogen and cooledto -70° C. in an isopropyl alcohol-dry ice bath.Methyltriphenylphosphonium bromide (3.8 g, 10.6 mmol) was addedportionwise over the course of 10 minutes. After complete addition, thereaction was stirred at -65° C. for one hour and was then allowed togradually warm up to ambient temperature, where it was stirred for anadditional 3.5 hours. The reaction was cooled to 0° C., and a solutionof1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanoneprepared as in Example 3 above (4.7 g, 0.0110 mol) dissolved intetrahydrofuran (50 ml) was added, dropwise, over the course of 30minutes. After the addition was complete, the reaction was stirred atambient temperature for 19 hours. The reaction was poured into water andthe aqueous mixture was extracted with diethyl ether. The diethyl etherextract was washed several times with water, dried with MgSO₄ andconcentrated to yield 7.0 g of a light orange solid. Recrystallizationfrom toluene-hexane provided 1.4 g of triphenylphosphine oxide andconcentration of the filtrate afforded 5.5 g of a glassy, beige solid.This was combined with an additional sample (6.5 g total) andpurification by preparative HPLC (Water's Associates prep LC/System 500)gave 5.2 g of a beige solid, which remained contaminated bytriphenylphosphine oxide. The compound was taken up in anhydrous ethanol(300 ml) and methanol (5 drops) and ethereal HCl was added toprecipitate 4.0 g of a pale, white solid, m.p.=192-194° C.

ANALYSIS: Calculated for C₂₅ H₃₀ ClFN₂ O₃ : 65.14% C 6.56% H 6.08% N;Found: 64.95% C 6.62% H 6.04% N

EXAMPLE 81(E)-1-[4-[[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2butenyl]oxy]-3-methoxyphenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10mmol), K₂ CO₃ (2 g), (E)-4[(4-bromo-2-butenyl)oxy]-3-methoxyacetophenone(4.0 g, 1.3 eq) in acetonitrile (100 ml) was heated at reflux for 2hours. At the end of the reaction, the solvent was removed on the rotaryevaporator. The residue was extracted into dichloromethane (300 ml). Theinsolubles were filtered off. The dichloromethane was concentrated. Thecrude product was purified on a flash chromatography column. The producteluted as an oil, weight 2.87 g (64%). Recrystallization fromethanol:hexane (20 ml:5 ml) gave(E)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-3-methoxy-phenyl]ethanoneas off-white crystals: 2.46 g; m.p.=91-93° C.

ANALYSIS: Calculated for C₂₅ H₂₇ FN₂ O₄ : 68.48% C 6.21% H 6.39% N;Found: 68.28% C 6.12% H 6.27% N

EXAMPLE 82 (Z)-1-[4-[(4-Chloro-2-butenyl)oxy]-3methoxyphenyl]ethanone

A stirred mixture of 4-hydroxy-3-methoxyacetophenone (16.6 g, 10 mmole),(K₂ CO₃ (14 g, 100 mmol) and cis-1,4-dichloro-2-butene (Aldrich, 15 g,120 mmol) in acetonitrile (250 ml) was heated at reflux for 2.5 hours.The mixture was filtered and concentrated to an oil. Purification was byflash chromatography. The fractions containing the purest product werecombined and concentrated to give white crystals, 7.7 g, 30%. This wasrecrystallized from ether to give analytical pure(Z)-1-[4[(4-chloro-2-butenyl)oxy]-3-methoxyphenyl]ethanone (2.72 g),m.p.=64-66° C.

ANALYSIS: Calculated for C₁₃ H₁₅ ClO₃ : 61.30% C 5.94% H; Found: 61.28%C 5.94% H

EXAMPLE 83(Z)-1-[4-[[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-3-methoxyphenyl]ethanone

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2g, 10 mmol), K₂ CO₃ (1.8 g, 13 mmol) and(Z)-1-[4[(4-chloro-2-butenyl)oxy]-3-methoxy-phenyl]ethanone (3.43 g, 9.7mmol) in acetonitrile (100 ml) was heated at reflux for 11/2 hours. Atthe end of the reaction, the solvent was removed and the inorganics werefiltered after addition of dichloromethane (250 ml). The dichloromethanesolvent was removed again. The crude oil was purified on two flashchromatography columns to give a colorless oil (2.78 g). The oil wassolidified by vigorously drying on a vacuum pump. Recrystallization fromethanol (10 ml) and hexane (2 ml) gave analytically pure(Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-3-methoxy-phenyl]ethanone,1.83 g,m.p.=57-59° C.

ANALYSIS: Calculated for C₂₅ H₂₇ FN₂ O₄ : 68.48% C 6.21% H 6.39% NFound: 68.26% C 6.18% H 6.32% N

EXAMPLE 84(E)-1-[3-[[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-hydroxyphenyl]ethanonehydrochloride

The mixture of(E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-benzyloxyphenyl]ethanone(5.5 g, 10.7 mmol), acetic acid (50 ml), and hydrochloric acid (6 ml)was heated at 75° C. for 2 hours. At the end of reaction, the solventwas reduced to about 20 ml on a rotary evaporator. The solution waspoured into ice water (350 ml) and extracted with dichloromethane (3×250ml). The dichloromethane solution was washed with brine and dried overNa₄ SO₄. A solid formed on concentration of the solvent. This wascollected by filtration (3.4 g). Recrystallization from hot methanol (40ml) gave 1.82 g of(E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4hydroxyphenyl]ethanonehydrochloride as white crystals, 37.5%, m.p.=208-210° C.

ANALYSIS: Calculated for C₂₄ H₂₅ FN₂ O₄.HCl: 62.54% C 5.69% H 6.08% N;Found: 62.40% C 5.60% H 6.04% N

EXAMPLE 85(E)-1-[3-[[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-benzyloxyphenyl]ethanone

(A) (E)-3-[(4'-bromo-2'-butenyl)oxy-4-benzyloxyacetophenone

To 4-benzyloxy-3-hydroxyacetophenone (17.6 g) in acetonitrile (200 ml)was added potassium carbonate (10 g), followed by the addition of(E)-1,4-dibromobutene (19 g). The resulting mixture was heated at refluxfor 3 hours. The mixture was concentrated, extracted intodichloromethane, and the potassium salt was removed by filtration.Solvent was removed, and the resulting material was purified by flashchromatography to yield 20.5 g of(E)-3-[(4'-bromo-2'-butenyl)oxy]-4-benzyloxyacetophenone as whitecrystals.

(B)(E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy-4-benzyloxyphenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.62 g, 25.5mmol), K₂ CO₃ (4 g, 29 mmol), and(E)-3-[(4'-bromo-2'-butenyl)oxyl-4-benzyloxy-acetophenone (10 g, 26.6mmol) in acetonitrile (125 ml) was heated at reflux for 3.5 hours. Themixture was cooled and concentrated to a crude solid. The residue wasextracted into dichloromethane (300 ml) and insolubles were filtered.The crude material from the dichloromethane solution was purified on aflash chromatography column. The product thus purified weighed 8 g as apale white solid. Recrystallization from hot ethanol gave 7.11 g of(E)-1-[3-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-4-benzyloxyphenyl]ethanoneas off-white crystals, m.p.=124-125° C.

ANALYSIS: Calculated for C₃₁ H₃₁ FN₂ O₄ : 72.36% C 6.07% H 5.44% N;Found: 72.23% C 6.04% H 5.04% N

EXAMPLE 866-Fluoro-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole

(A) 6-(3-Chloropropoxy)-5-methoxyindole

To a stirred suspension of sodium hydride (0.94 g, 19.6 mmol of a 50%oil dispersion) in dimethylformamide (20 ml) under nitrogen and cooledto -5° C. was added, dropwise, 5-methoxy-6-hydroxyindole (3.2 g, 19.6mmol) dissolved in dimethylformamide (60 ml) so that the temperature didnot exceed -2° C. After complete addition, the reaction was stirred for45 minutes at 0° C. While maintaining the reaction temperature between-5° C. and 0° C., a solution of 1-bromo-3-chloropropane (3.1 g, 19.6mmol) dissolved in dimethylformamide (15 ml) was slowly added. Themixture was stirred at ambient temperature under nitrogen for 21 hours.The reaction was cooled in an ice bath, and water was added to destroythe excess sodium hydride, and the aqueous mixture was extracted withethyl acetate. The ethyl acetate extract was washed with water, driedwith MgSO₄ and concentrated to yield 5.3 g of a dark, oily liquid. Thiswas combined with an additional sample, for a total of 10.0 g, andpurification by preparative HPLC (Waters Associates prep LC/System 500)provided 5.1 g of a brown solid. A 2.5 g sample was recrystallized fromisopropyl alcohol to yield 1.1 g (30%) of6-(3-chloropropoxy)-5-methoxyindole as beige crystals, m.p.=73-75° C.

ANALYSIS: Calculated for C₁₂ H₁₄ ClNO₂ : 60.13% C 5.89% H 5.84% N;Found: 60.26% C 5.86% H 5.77% N

(B)6-Fluoro-3-[1-[3-[(5-methoxy-1H-indol-6-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.5 g, 11.5mmol), 6-(3-chloropropoxy)-5-methoxyindole (2.5 g, 10.4 mmol), K₂ CO₃(1.6 g, 11.5 mmol), KI (200 mg) and acetonitrile (100 ml) was stirred atreflux under nitrogen for 40 hours. The cooled reaction was poured intowater and extracted with ethyl acetate. The ethyl acetate extract waswashed with water, washed with brine, dried with MgSO₄ and concentratedto yield 4.0 g of a solid. The compound was recrystallized from ethanolto afford 3.3 g. Another recrystallization from ethanol (utilizing acharcoal treatment) provided 2.9 g (66%) of6-fluoro-3-[1-[3-[(5-methoxy-1H-indol-6yl)oxy]-propyl]-4-piperidinyl]-1,2-benzisoxazoleas a beige solid, m.p.=156-158° C.

ANALYSIS: Calculated for C₂₄ H₂₆ FN₃ O₃ : 68.07% C 6.19% H 9.92% N;Found: 67.89% C 6.07% H 9.91% N

EXAMPLE 876-Fluoro-3-[1-[3-[(1H-indol-7-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazolehemifumarate

(A) 7-(3-Chloropropoxy)indole

To a stirred suspension of sodium hydride (0.8 g, 17 mmol of a 50% oildispersion) in dimethylformamide (20 ml), under nitrogen, was addeddropwise 7-hydroxyindole (2.1 g, 15.7 mmol) in dimethylformamide (20ml). After complete addition, the reaction was stirred at ambienttemperature for 0.5 hour and then cooled to 15° C. To this cooledsolution was added, dropwise, 1-bromo-3-chloropropane (2.5 g, 15.7 mmol)in dimethylformamide (5 ml). The reaction was then stirred at ambienttemperature for 16 hours. The reaction was poured into water, and theaqueous suspension extracted with ethyl acetate. The ethyl acetate waswashed with water, dried (MgSO₄), and the solvent was concentrated toafford a dark brown oil. Following flash chromatography on silica gel,7-(3chloropropoxy)indole was obtained as a colorless oil, 1.0 g.

ANALYSIS: Calculated for C₁₁ H₁₂ ClNO: 63.01% C 5.77% H 6.68% N; Found:63.25% C 5.61% H 6.65% N

(B)6-Fluoro-3-[1-[3-[(1H-indol-7-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazolehemifumarate

A stirred mixture of 7-(3-chloropropoxy)-1H-indole (3.5 g, 17 mmol),6-fluoro-(4-piperidinyl)-1,2-benzisoxazole (3.5 g, 17 mmol), K₂ CO₃ (2.3g) and acetonitrile (60 ml) was refluxed for 11 hours. The reaction waspoured into water, and the aqueous mixture was extracted with ethylacetate. The ethyl acetate was washed with water, dried (MgSO₄), and thesolvent was concentrated to afford a dark oil. The oil was flashchromatographed on silica gel. Upon concentration of the appropriatefractions, 3.0 g of a white, foamy substance was obtained. The substancewas dissolved in ethyl acetate (75 ml) and fumaric acid (0.97 g, 83mmol) was added. The mixture was briefly heated to reflux, and thenstirred at ambient temperature for 1.5 hours. The resultant insolublewhite fumarate salt was collected and afforded 4.2 g of product.Recrystallization of the salt from dimethylformamide yielded 3.1 g (36%)of6-fluoro-3-[1-[3-[(1H-indol-7-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazolehemifumarate as a white solid, m.p.=213-215° C.

ANALYSIS: Calculated for C₂₅ H₂₆ FN₃ O₄ : 66.50% C 5.80% H 9.31% N;Found: 66.23% C 6.14% H 9.39% N

EXAMPLE 886-Fluoro-3-[1-(3-hydroxypropyl)4-piperidinyl]-1,2-benzisoxazole

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10.0g, 45 mmol), K₂ CO₃ (10.0 g), 3-bromo-1-propanol (7.3 g, 46 mmol) andacetonitrile (200 ml) was refluxed for 3 hours. The reaction was pouredinto H2 and 7.1 g of a beige solid was collected. The filtrate wasextracted with dichloromethane, and after concentration an additional6.7 g of crude solid was harvested. The solids were combined andtriturated with refluxing ethyl acetate to afford 8.0 g of6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole as anoff-white solid. A sample (4.0 g) was recrystallized from ethanol-water(with charcoal treatment) to yield 2.4 g (40%) of the alcohol as a whitesolid, m.p.=140-142° C.

ANALYSIS: Calculated for C₁₅ H₁₉ FN₂ O₂ : 64.73% C 6.88% H 10.06% NFound: 64.79% C 6.97% H 10.03% N

EXAMPLE 896-Fluoro-3-[1-(2-pyrimidinoxy)propyl]-4-piperidinyl]-1,2-benzisoxazolefumarate

To a stirred suspension of6-fluoro-3-[1-(3hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole (3.6 g,13 mmol) in tetrahydrofuran (50 ml) was added dropwise, potassiumbistrimethylsilylamide (2.6 g, 13 mmol) dissolved in tetrahydrofuran (20ml). After complete addition, the reaction was stirred at ambienttemperature for 5 min, and then 2-chloropyrimidine (1.6 g, 14 mmol) wasadded. The reaction was stirred at ambient temperature for 4 hours, andTLC at this time indicated an incomplete reaction. An additionalquantity of the base (0.5 g) was added, and the reaction was allowed toproceed at ambient temperature for 14 additional hours. The reaction waspoured into water and the aqueous mixture was extracted withdichloromethane. The extract was washed (H₂ O), dried (K₂ CO₃), and thesolvent was concentrated to afford a wet solid. The solid was trituratedwith diethyl ether and the product that separated was collected to yield1.0 g of the starting alcohol. The filtrate was then concentrated toafford 3.8 g of a waxy, yellow solid. This material was combined with2.6 g from another run and the combined sample flash chromatographed onsilica gel, eluting first with ethyl acetate and then with 8%diethylamine-ethyl acetate. Concentration of the appropriate fractionsafforded 3.0 g of the desired compound as a yellow solid. The solid wasconverted to a fumarate salt with fumaric acid in acetone, and thenreversed to its free base. It was combined with another sample and thecombined sample (3.8 g) chromatographed on silica gel on HPLC (4.5%methanol-dichloromethane as eluent). Concentration of the appropriatefractions yielded 1.6 g of a yellow solid. A fumarate salt was preparedto yield 2.1 g (16%) of6-fluoro-3-[1-[(2-pyrimidinoxy)-propyl]-4piperidinyl]-1,2-benzisoxazolefumarate, m.p.=184-186° C.

ANALYSIS: Calculated for C₂₃ H₂₅ FN₄ O₆ : 58.47% C 5.33% H 11.86% NFound: 58.52% C 5.34% H 11.80% N

EXAMPLE 906-Aceto-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan

(A) 6-aceto-2-mesyloxymethyl-1,4-benzodioxan

6-Aceto-2-hydroxymethyl-1,4-benzodioxan (3.39 g, 16.3 mmol) wasdissolved in trichloromethane (100 ml). Triethylamine (2.5 g) was addedto mesylchloride (2.5 g, 1.35 eq) at 0° C. The mixture was stirred for 2hours at room temperature. The mixture was then diluted, washed with anice/dilute hydrochloric acid mixture (150 ml), washed with sodiumbicarbonate and brine, dried over magnesium sulfate, and concentrated toyield 5.6 g. Following chromatography on a SiO₂ column, 3.64 g (78%yield) of 6-aceto-2-mesyloxy-methyl-1,4-benzodioxan were obtained.

(B)6-aceto-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0g, 13.6 mmol), K₂ CO₃ (2 g, 14.5 mmol) and6-aceto-2-mesyloxymethyl-1,4-benzodioxan (3.5 g, 12 mmol) inacetonitrile (100 ml) was heated at reflux for 3 hours. At the end ofthe reaction the solvent was removed on a rotary evaporator. The residuewas extracted into dichloromethane (350 ml) and the insolubles werefiltered off. The dichloromethane solution was concentrated and thecrude oil was purified by flash chromatography. The product thusobtained weighed 3.38 g (59%). Recrystallization from ethanol gave6-aceto-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxanas light yellow crystals (3.2 g), m.p.=122-123° C.

ANALYSIS: Calculated for C₂₃ H₂₃ FN₂ O₄ : 67.31% C 5.65% H 6.83% NFound: 67.24% C 5.50% H 6.75% N

EXAMPLE 912-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan

A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0g, 13.6 mmol), K₂ CO₃ (2.45 g, 17.7 mmol),2-methanesulfonyloxymethyl-1,4-benzodioxan (3.35 g, 13.7 mmole) inacetonitrile (100 ml) was heated at reflux for 12 hours. At the end ofthe reaction, the insolubles were filtered and rinsed withdichloromethane. The organic solution was concentrated. The crude oilwas purified by flash chromatography on a silica gel column. Thefractions containing the pure product were pooled and concentrated to alight yellow oil (3.94 g, 74%). Crystallization from ethanol andpetroleum ether gave2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxanas off-white crystals, 2.22 g, m.p.=86-87° C.

ANALYSIS: Calculated for C₂₁ H₂₁ FN₂ O₃ : 68.47% C 5.75% H 7.60% N;Found: 68.33% C 5.75% H 7.51% N

EXAMPLE 922-[4(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,4-benzodioxan

(A) 2-mesyloxyethyl-1,4-benzodioxan

To the compound 2-hydroxyethyl-1,4-benzodioxan (11.96 g) indichloromethane (450 ml) was added triethylamine (0.12 mol, 10 ml).Mesylchloride (9.2 g) was then added dropwise and the reaction mixturewas stirred for one hour at room temperature. After completion of thereaction, the solution was washed with water, brine, and concentrated toan oil, which was purified by chromatography on silica gel to yield2-mesyloxyethyl-1,4-benzodioxan, 17.08 g.

(B)2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-pipendinyl]ethyl]-1,4-benzodioxan

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.7 g, 21mmol), K₂ CO₃ (3.5 g, 25.4 mmol) and 2-mesyloxyethyl-1,4-benzodioxan(5.5 g, 21.3 mmol) in acetonitrile (250 ml) was heated at reflux for 3.5hours. At the end of the reaction, insolubles were filtered. The solidwas washed with dichloromethane (200 ml). The solutions were combinedand evaporated to an oil. This crude oil was purified by flashchromatography on a silica gel column. The material thus obtained wascrystallized from ethanol. The2-[4(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,4-benzodioxancrystals were collected and weighed 3.8 g, 48%, m.p.=112-113° C.

ANALYSIS: Calculated for C₂₂ H₂₃ FN₂ O₃ : 69.09% C 6.06% H 7.32% N;Found: 69.17% C 6.02% H 7.31% N

EXAMPLE 936-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-7-methoxy-1-tetralone

(A) 6-(3-chloropropoxy)-7-methoxy-1-tetralone

A mixture of 6-hydroxy-7-methoxy-1-tetralone (J. Org. Chem., 1985, 50,4937) (1.5 g, 7.8 mmol), K₂ CO₃ (1.7 g, 12.3 mmol), and acetone (30 ml)was stirred at reflux under nitrogen for 45 minutes. The reaction wascooled to ambient temperature and a solution of 1-bromo-3-chloropropane(1.9 g, 12.1 mmol) dissolved in 8 ml acetone was dripped into themixture. After total addition, the reaction was heated to reflux andstirred under nitrogen for 21 hours. The reaction was cooled to ambienttemperature and filtered. The filter cake was washed well with acetoneand the filtrate was concentrated to yield 2.0 g6-(3-chloropropoxy)-7-methoxy-1-tetralone as an amber oil.

(B)6-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-7-methoxy-1-tetralone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (0.78 g, 3.6mmol), K₂ CO₃ (0.60 g, 4.1 mmol), KI (100 mg),6-(3-chloropropoxy)-7-methoxy-1-tetralone (0.87 g, 3.2 mmol), andacetonitrile (50 ml) was stirred at reflux under nitrogen for 17 hours.The cooled reaction was poured into 100 ml of water and the aqueousmixture was extracted with ethyl acetate. The ethyl acetate extract waswashed with brine, dried with MgSO₄ and concentrated to yield 1.7 g of abrown oil. The oil was purified by preparative HPLC (Waters AssociatesPrep LC/system 500) to afford 1.0 g of a light brown solid. This wascombined with an additional sample (2.3 g total) and recrystallizationfrom ethanol yielded 1.7 g. A subsequent recrystallization from ethanolgave 1.25 g (36%) of6-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-7-methoxy-1-tetraloneas a beige powder, m.p.=129-131 ° C.

ANALYSIS: Calculated for C₂₆ H₂₉ FN₂ O₄ : 69.01% C 6.46% H 6.19% N;Found: 68.77% C 6.43% H 6.16% N

EXAMPLE 94N-[3-[4-(6-Fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propyl]-6-acety-2-benzoxazolinone

(A) N-(3-chloropropyl)-2-benzoxazolinone

To a stirred suspension of sodium hydride (7.8 g, 160 mmol,ether-washed) in dimethylformamide (75 ml) was added dropwise undernitrogen, 2-benzoxazolinone (20.0 g, 150 mmol) dissolved indimethylformamide (150 ml). After complete addition the reaction wasstirred at ambient temperature for 30 min, and then it was cooled to -5°C. with an ice-acetone bath. A solution of 3-chloro-1-bromopropane (46.6g, 300 mmol) in dimethylformamide (50 ml) was added dropwise(temperature never exceeded 0° C.). The reaction was allowed to reachambient temperature and was stirred for 16 hours. The reaction waspoured into water, and the aqueous mixture was extracted with ethylacetate. The ethyl acetate was washed with water, dried (MgSO₄), and theextract concentrated to afford 21.9 g of a brown solid. The solid wasrecrystallized from toluene-hexane to affordN-(3-chloropropyl)-2-benzoxazolinone as large needles, 15.6 g,m.p.=264-266° C.

(B) N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone

A mixture of N-(3-chloropropyl)-2-benzoxazolinone (8.5 g, 40 mmol),polyphosphoric acid (100 g), and acetic acid (2.4 g, 2.3 ml, 40 mmol),was stirred and heated at 100° C. for 2 hours. The hot solution waspoured into ice-water to deposit a yellow gum. The mixture was extractedwith dichloromethane, and insolubles were filtered. The dichloromethaneextract was washed with water, dried (K₂ CO₃), and concentrated toafford 6.4 g of a slightly green solid. This was recrystallized fromethanol (95%) to yield N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone asa brown solid, 3.5 g, m.p.=100-103° C.

N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-6acetyl-2-benzoxazolinone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9mmol), N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone (2.4 g, 9 mmol), K₂CO₃ (3.6 g), a few crystals of KI, and acetonitrile (50 ml) was stirredand refluxed for 13 hours. The reaction was poured into water, and adark, brown solid that separated was collected to afford 3.3 g of crudeproduct. The solid was chromatographed on a Waters Prep 500 HPLC.Concentration of appropriate fractions afforded 2.3 g of a yellow solid,and recrystallization from ethyl acetate yielded 1.2 g (31%) ofN-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-6-acetyl-2-benzoxazolinone,m.p.=152-154° C.

ANALYSIS: Calculated for C₂₄ H₂₄ FN₃ O₄ : 65.89% C 5.53% H 9.61% NFound: 65.67% C 5.48% H 9.52% N

EXAMPLE 95N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]phthalimide

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (6.44 g, 29.1mmole), K₂ CO₃ (6.4 g, 46 mmol), N-(3-bromopropyl)phthalimide (8.4 g, 31mmol) in acetonitrile (150 ml) was heated at reflux for 3.5 hours. Theinsolubles were filtered. The solvent was removed at reduced pressureand the residue was purified by silica gel column chromatography to giveN-[3-[4-(6fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]phthalimideas a white solid. Recrystallization from ethanol yielded 9.8 g (83%) ofoff-white crystals, m.p.=129-130° C.

ANALYSIS: Calculated for C₂₃ H₂₂ FN₃ O₃ : 67.89% C 5.44% H 10.31% N;Found: 67.49% C 5.38% H 10.13% N

EXAMPLE 961-(3-Aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinedihydrochloride

A mixture ofN-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propyl]phthalimide(8.5 g, 21 mmol), hydrazine monohydrate (1.5 g, 30 mmol) in methanol (60ml) was heated at reflux for 2 hours. At the end of the reaction,methanol was removed to leave a crude solid. To this was added water (60ml), then the mixture was acidified with HCl to pH 1. The insolubleswere filtered with the aid of a pad of Celite. The aqueous solution wasbasified with 50% NaOH, (pH 13), then extracted with dichloromethane.The combined dichloromethane solution was washed with brine, then driedto a colorless oil (4.5 g). The analytical sample (1.5 g) was preparedby treating the oil with HCl in ethanol at 0° C. The1-(3-aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinedihydrochloride was obtained as white crystals, 2.03 g, m.p.=231-234° C.

ANALYSIS: Calculated for C₁₅ H₂₀ FN₃ O.2HCl: 51.44% C 6.33% H 12.00% N;Found: 51.35% C 6.49% H 11.90% N

EXAMPLE 97cis-2-[3-[4-(6-Fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propyl]hexahydro-1H-isoindole-1,3-dionehydrochloride

A mixture of1-(3aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.01 g,10.8 mmol) and cis-1,2-cyclohexane-dicarboxylic anhydride (1.9 g, 12.3mmol) in dry pyridine (30 ml) was heated at reflux for 16 hours. Thedark brown solution was concentrated to dryness on a rotary evaporator.The crude residue was purified twice by flash chromatography over asilica gel column. The pure product thus obtained weighed 2.5 g (67%).This was converted to the hydrochloride salt by treatment with HCl inethanol (50 ml). Thecis-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-hexahydro-1H-isoindole-1,3-dionehydrochloride crystals so obtained weighed 3.0 g, m.p.=242-245° C.

ANALYSIS: Calculated for C₂₃ H₂₈ FN₃ O₃.HCl: 61.14% C 6.50% H 9.34% N;Found: 61.32% C 6.32% H 9.27% N

EXAMPLE 98N-[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimide

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.5 g, 25mmol), 4-bromobutylphthalimide (8.0 g, 28.3 mmol, 1.13 eq), K₂ CO₃ (4.55g, 32 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours.At the end of the reaction, the mixture was filtered. The insolubleswere washed with dichloromethane (200 ml). The organic solution wasconcentrated gradually to allow cystallization. The crude crystals (5.9g) were collected. The mother liquor was concentrated to a solid (5.5g). Purification was by flash chromatography over a silica gel column.The product (3.8 g) thus purified was recrystallized from ethanol (70ml) to give 2.48 g ofN-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimideas white crystals, m.p.=144-146° C.

ANALYSIS: Calculated for C₂₄ H₂₄ FN₃ O₃ : 68.39% C 5.74% H 9.97% N;Found: 68.34% C 5.74% H 9.84% N

EXAMPLE 99 1-(4-Aminobutyl)4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinedihydrochloride

A mixture of N-[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinyl]-butyl]phthalimide (6.9 g, 16.4 mmol) and hydrazinemonohydrate (1.64 g, 32.8 mmol) in methanol (70 ml) was heated at refluxfor 3 hours. At the end of the reaction, methanol was removed to leave acrude solid. This was dissolved in water and acidified with HCl to pH 2.The insolubles were filtered. The aqueous solution was basified with 50%NaOH, and then extracted with dichloromethane. The dichloromethanesolution was washed with water and brine, and then dried over MgSO₄. Thesolvent was removed to a colorless oil: 4.48 g. This oil was treatedwith 2.5 equivalents of HCl in ethanol. The solid was collected.Recrystallization from ethanol (65 ml) and methanol (20 ml) gave 2.0 gof 1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinedihydrochloride as white crystals, m.p.=234-237° C.

ANALYSIS: Calculated for C₁₆ H₂₂ FN₃ O₃.2HCl: 52.75% C 6.64% H 11.53% N;Found: 52.37% C 6.59% H 11.07% N

EXAMPLE 100cis-2-[4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]hexahydro-1H-isoindole-1,3-dionehydrochloride

A mixture of1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.7 g,16.1 mmol) and cis-1,2-cyclohexanedicarboxylic anhydride (3.23 g, 21mmol) in pyridine (45 ml) was heated at reflux for 8 hours. At the endof the reaction, pyridine was removed to dryness. The crude product waspurified on a silica gel column. The material thus obtained weighed 3.18g (45%) as a clear oil. This oil was dissolved in ethanol (15 ml), thenwas treated with HCl in ethanol (45 ml). Crystallization took place uponcooling. The crystals were collected, 3.2 g, m.p.=229-231° C.

ANALYSIS: Calculated for C₂₄ H₃₀ FN₃ O₃.HCl: 62.13% C 6.73% H 9.06% N;Found: 61.79% C 6.68% H 8.92% N

EXAMPLE 1011-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]thio]-3-methoxyphenyl]ethanone

(A) 1-[4-[(3-chloropropyl)thio]-3-methoxyphenyl]ethanone

A mixture of 1-(4-thio-3-methoxyphenyl)ethanone (10.0 g, 54.9 mmol),potassium carbonate (9.0 g, 65.1 mmol), and acetone (100 ml) was stirredat reflux under nitrogen for 30 minutes. The reaction was cooled toambient temperature and a solution of 1-bromo-3-chloropropane (6.5 ml,9.5 g, 60.4 mmol) dissolved in acetone (25 ml) was dripped into thereaction. After complete addition, the reaction was heated to reflux andstirred under nitrogen for 17 hours. After the reaction was carried tosubstantial completion, the reaction mixture was filtered and theresulting filter cake was washed with acetone. The filtrate wasconcentrated to provide an amber oil. A small sample was solidified bytrituration with hot cyclohexane to provide1-[4-[(3-chloropropyl)thio]-3-methoxyphenyl]ethanone as a yellow solid,11.7 g, m.p.=53-55° C.

(B)1-[4-[[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-thio]-3-methoxyphenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6mmol), 1-[4-[(3-chloropropyl)-thio]-3-methoxyphenyl]ethanone (3.5 g,13.6 mmol), K₂ CO₃ (2.3 g, 16.6 mmol), KI (200 mg) and CH₃ CN (100 ml)was stirred at reflux under nitrogen for 7.5 hours and then was left atambient temperature for 65 hours. The reaction was poured into water andthe aqueous mixture was extracted with ethyl acetate. The ethyl acetateextract was washed twice with water, once with brine and dried overMgSO₄. The solvent was removed in vacuo to afford 6.8 g of a light brownoil. The sample was purified by flash chromatography. Concentration ofappropriate fractions yielded 3.0 g. Recrystallization from ethanolprovided 2.4 g (41%) of1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]thio]-3-methoxyphenyl]-ethanoneas a beige solid, m.p.=93-95° C.

ANALYSIS: Calculated for C₂₄ H₂₇ FN₂ O₃ S: 65.14% C 6.15% H 6.33% N;Found: 64.66% C 6.17% H 6.26% N

EXAMPLE 1024-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-(2'-methoxyphenyl)butylpiperidinemaleate

(A) 2-(4-bromobutyl)anisole

2-Bromoanisole (2.0 g, 1.07 mmol) in tetrahydrofuran (20 ml) was cooledto -78° C. under nitrogen and secondary butyllithium (1.3M, 10 ml, 1.3eq) was charged into the resulting solution for two hours. The solutionwas quenched with 1,4-dibromobutane (3.2 g) and allowed to stir atambient temperature overnight. The mixture was diluted with ethylacetate, washed with water and brine, and concentrated to an oil.Following chromatography on a SiO₂ column, 2.4 g of2-(4-bromobutyl)anisole were obtained.

(B)4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-(2'-methoxyphenyl)butyl-piperidinemaleate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.36 g, 10.7mmole), K₂ CO₃ (2 g, 14.5 mmol) and 2-(4-bromobutyl)anisole (2.4 g, 10mmol) in acetonitrile (100 ml) was heated at reflux for 2.5 hours. Atthe end of reaction, the solvent was removed. The residue was extractedinto dichloromethane (200 ml) and filtered. The dichloromethane solutionwas concentrated. The crude oil obtained was purified on a flashchromatography column. The material thus purified was a light yellow oil(2.73 g, 53%). This oil was dissolved in ethanol and treated with maleicacid (607 mg, 1.0 eq) in ethanol. The4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-(2'-methoxyphenyl)-butylpiperdinemaleate crystals formed on concentration and subsequent cooling to 0° C.These were collected and dried to yield 2.05 g, m.p.=132-133° C.

ANALYSIS: Calculated for C₂₃ H₂₇ FN₂ O₂.C₄ H₄ O₄ : 65.05% C 6.27% H5.62% N; Found: 65.25% C 6.30% H 5.70% N

EXAMPLE 1031-[4-(1,3Dithian-2-yl)ethyl]phenyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)butylpiperidine

(A) 4-bromo-1-(1,3-dithian-2-yl)ethylbenzene

To the compound p-bromoacetophenone (36.85 g, 185 mmol) intrichloromethane (300 ml) was added 1,3-propanedithiol (25 g, 230 mmol)and boron trifluoride etherate (3 ml). The resulting mixture was stirredat room temperature for 48 hours. The mixture was diluted withdichloromethane (500 ml), washed twice with 10% sodium hydroxide (200ml), water, and brine, and then dried (Na₂ SO₄). The product wasconcentrated to an oil. A portion was stirred with ether (100 ml) and acrystalline product was formed. The crystalline product was recovered byfiltration and purified by recrystallization to yield4-bromo-1-(1,3-dithian-2-yl)ethylbenzene.

(B) 4-(4-bromobutyl)-1-(1,3-dithian-2-yl)ethylbenzene

A solution of 4-bromo-1-(1,3-dithian-2-yl)ethylbenzene (27.2 g, 94 mmol)in tetrahydrofuran (200 ml) was charged with sec-butyllithium (99 ml,1.3M in cyclohexane, 0.13 mole) dropwise at -78° C. under nitrogen. Themixture was stirred at ambient temperature for 1.5 hours, and thenquenched with 1,4-dibromobutane (42 g, 0.2 mole). After being stirredfor 3 hours, the mixture was poured into ethyl acetate, and then washedwith water and brine. The organic solution was then dried (Na₂ SO₄) andconcentrated to an oil. The crude product was purified by flashchromatography over a silica gel column. The4-(4-bromobutyl)-1-(1,3-dithian-2-yl)-ethylbenzene thus purified was alight oil, 22.3 g.

ANALYSIS: Calculated for C₁₅ H₂₁ BrS₂ : 52.17% C 6.13% H; Found: 52.60%C 6.25% H

(C)1-[4-(1,3-dithian-2-yl)ethyl]phenyl4-(6-fluoro-1,2-benzisoxazol-3-yl)butylpiperidine

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.4 g, 24.5mmol), K₂ CO₃ (4.2 g, 30 mmol),4-(4-bromobutyl)-1-(1,3-dithian-2-yl)ethylbenzene (8.5 g, 24.6 mmol) inacetonitrile (200 ml) was heated at reflux for 2.5 hours. At the end ofthe reaction, the mixture was filtered and the solvent was concentrated.The crude (13 g) was purified by flash chromatography over a silica gelcolumn. The material thus purified (8.67 g; 72%) was recrystallized fromethanol (50 ml) and hexane (100 ml) to afford 6.6 g of1-[4-(1,3-dithian-2-yl)ethyl]phenyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)butylpiperidineas light yellow crystals, m.p.=108-110° C.

ANALYSIS: Calculated for: C₂₇ H₃₃ FN₂ OS₂ 66.91% C 6.86% H 5.78% N;Found: 66.72% C 6.76% H 5.71% N

EXAMPLE 1041-[4-(4'-Acetophenyl)butyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine

A solution of1-[4-(1,3-dithian-2-yl)ethylphenyl]butyl-4-(6fluoro-1,2-benzisoxazol-3-yl)piperidine(5.6 g, 11.6 mmol), water (5 ml), and methanol (30 ml), in acetone (50ml), was treated with mercury (II) perchlorate trihydrate (5 g, 1.1 eq.)at room temperature. After 30 minutes, the reaction was completed. Thesolids were filtered, and the solvent was removed on a rotaryevaporator. The crude product was dissolved in ethyl acetate (500 ml)and washed with water, brine, then dried over Na₂ SO₄. The solvent wasremoved to give a crude oil. The purification was by flashchromatography over a silica gel column. The oil thus obtained (2.67 g,50%) was combined with 1.1 g of oil prepared in the same fashion.Crystallization from ethanol (10 ml) and hexane (20 ml) yielded1-[4-(4'-acetophenyl)butyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidineas off-white crystals, 2.32 g, m.p.=85-86° C.

ANALYSIS: Calculated for C₂₄ H₂₇ FN₂ O₂ : 73.07% C 6.90% H 7.10% N;Found: 72.68% C 7.05% H 7.09% N

EXAMPLE 1051-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-methoxy-phenyl]ethanone

To a stirred suspension of sodium hydride (0.37 g, 7 mmol of a 50% oildispersion) in dimethylformamide (20 ml) was added, dropwise,1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-hydroxyphenyl]ethanone(2.9 g, 7 mmol) dissolved in dimethylformamide (25 ml). The reaction wasstirred at ambient temperature for 15 minutes, and then it was cooledwith an ice bath to about 5° C., whereupon methyl iodide (1.0 g, 7 mmol)in dimethylformamide (1 ml) was added dropwise. The reaction was stirredat ambient temperature for 30 min, and then water was added. Theresulting aqueous mixture was extracted with ethyl acetate, the extractwashed with water, dried (MgSO₄), and the solvent was concentrated toafford 4.9 g of a brown oil, which solidified on standing. The solid wasflash chromatographed on silica gel. The appropriate fractions wereconcentrated to yield 2.7 g of product as a yellow solid.Recrystallization from toluene-hexane yielded 2.0 g (67%) ofanalytically pure1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-methoxyphenyl]ethanoneas a yellow solid, m.p.=96-98° C.

ANALYSIS: Calculated for C₂₄ H₂₈ FN₃ O₃ : 67.75% C 6.63% H 9.88% N;Found: 67.93% C 6.72% H 9.80% N

EXAMPLE 106(2,4Difluorophenyl)-[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxalate

In a 1 liter round bottom flask, a solution ofethyl-N-benzyl-3-pyrrolidine carboxylate (21.8 g, 11.7 mmol) in 140 mlof 6N HCl was heated at reflux for 2.5 hours. The solution was cooledand the solvent was removed to dryness with a vacuum pump. The residuewas then treated with thionyl chloride (100 ml) for 16 hours at roomtemperature. After the reaction, the excess thionyl chloride was vacuumstripped to dryness (60° C., 4 hours). To the residue in the flask wasadded 1,3-difluorobenzene (30 g, 26 mmol) followed by aluminum chloride(25 g, 18.7 mmol) in portions at room temperature. When the mixtureturned homogeneous (in about 10 minutes) it was then heated at 55° C.for 1 hour. After the reaction was complete, excess 1,3l difluorobenzenewas removed under reduced pressure. The residue was partitioned betweenice/water and dichloromethane (700 ml) and basified with 50% NaOHsolution to pH 10. The dichloromethane solution was washed with waterand brine, then dried over anhydrous MgSO₄. The solvent was stripped andthe crude oil (31 g) was purified by flash chromatography over a silicagel column. The pure product thus obtained weighed 26 g (74%) as ayellow oil. An analytical sample was prepared by dissolving 4.2 g of theoil in ethanol and treating with an ethanol solution of oxalic acid(1.33 g, 14.8 mmol). To the mixture was added ether dropwise to causecrystallization. Recrystallization from ethanol and ether gave 2.63 g of(2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxalateas white crystals, m.p.=114-116° C.

ANALYSIS: Calculated for C₂₀ H₁₉ FNO₅ : 61.38% C 4.89% H 3.58% N; Found:61.16% C 4.80% H 3.60% N

EXAMPLE 1076-Fluoro-3-[1-phenylmethyl)-3-pyrrolidinyl]-1,2-benzisoxazole fumarate

(A) (2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]-methanoneoxime

To the compound(2,4-difluorophenyl)[l-(phenylmethyl)-3-pyrrolidinyl]methanone (22 g) in95% ethanol (350 ml) and water (100 ml) was added NH₂ OH.HCl (10.1 g)and ammonium acetate (12.7 g, 2.1 eq). The resulting mixture wasrefluxed for 3.5 hours. The mixture was then allowed to stir at roomtemperature for 24 hours. The reaction mixture was concentrated toremove ethanol, poured into water (500 ml), and extracted withdichloromethane (500 ml). This was followed by washing with water,brine, and drying over magnesium sulfate. The product was concentratedto an oil and purified by column chromatography to yield 12 g of(2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxime.

(B) 6-fluoro-3-[1-(phenylmethyl)-3-pyrrolidinyl]-1,2-benzisoxazolefurmarate

A mixture of(2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxime(10.8 g, 34.2 mmol), potassium hydroxide (10 g), water (100 ml), andethanol (100 ml) was heated at reflux for 2 hours. At the end of thereaction, the solution was cooled and ethanol was removed on a rotaryevaporator. The aqueous mixture was diluted with water (100 ml) thenextracted with dichloromethane (500 ml). The organic solution was washedwith brine and dried over anhydrous MgSO₄. The solution was concentratedto an oil (9.8 g). The crude product was purified by flashchromatography over a silica gel column. The product thus obtainedweighed 4.46 g (44%) as a light yellow oil. The oily product wasdissolved in ethanol, and then treated with a solution of fumaric acid(1.73 g, 1.0 eq) in ethanol. Crystallization took place slowly with theaddition of isopropyl ether. Recrystallization from ethanol (15 ml) gave4.6 g of 6-fluoro-3-[1-(phenylmethyl)-3-pyrrolidinyl]-1,2-benzisoxazolefumarate as white crystals, m.p.=142-144° C.

ANALYSIS: Calculated for C₂₂ H₂₁ FN₂ O₅ : 64.07% C 5.13% H 6.81% N;Found: 64.11% C 5.05% H 6.89% N

EXAMPLE 108 (E)-1-[4-[(4-bromo-2-butenyl)oxy]-3-methoxyphenyl]ethanone

A mixture of 4-hydroxy-3-methoxyacetophenone (10 g, 59 mmol), K₂ CO₃ (10g, 1.2 q) and 1,4-dibromo-2-butene (>95% trans, Aldrich, 18 g, 1.2 eq)in acetone (500 ml) was heated at 55° C. for 3 hours. At the end of thereaction, the solvent was concentrated. The crude product was extractedinto dichloromethane (750 ml) and the insolubles were filtered; then thesolution was concentrated again to an oil. Purification on a silica gelcolumn (SiO₂, 100 g, eluted with dichloromethane) yielded 7.25 g (40%)of white solid. Recrystallization from ether gave analytically pure(E)-1-[4-[(4bromo-2-butenyl)oxy]-3methoxyphenyl]ethanone (3.91 g),m.p.=71-72° C.

ANALYSIS: Calculated for C₁₃ H₁₅ BrO₃ : 52.19% C 5.50% H; Found: 52.12%C 4.94% H

EXAMPLE 109 4-(3Chloropropoxy)-3-methoxybenzaldehyde

A mixture of vanillin (30.4 g, 200 mmol), K₂ CO₃ (27.6 g) and acetone(150 ml) was stirred and refluxed for 0.5 hours. Heating was removed and1-bromo-3-chloropropane (40.8 g, 260 mmol) in acetone was addeddropwise. The reaction was stirred and refluxed for 16 hours, and thenit was poured into water. The aqueous mixture was extracted with diethylether, the extract was dried (MgSO₄), and the solution was concentratedto afford an oil, which upon evacuation solidified to a white solid(50.2 g). An 8.0 g sample was flash chromatographed on silica gel with50% ethyl acetatehexane as eluent. Concentration of appropriatefractions gave 2.7 g (37%) of 4-(3-chloropropoxy)-3-methoxybenzaldehydeas a white solid, m.p.=53-55° C.

ANALYSIS: Calculated for C₁₁ H₁₃ ClO₃ : 57.78% C 5.73% H; Found: 57.21%C 5.52% H

EXAMPLE 110 6-Fluoro-3-(3-pyrrolidinyl)-1,2-benzisoxazole hydrochloride

A mixture of 3-(6-fluoro-1,2-benzisoxazol-3-yl)-1-pyrrolidinylcarboxylicacid ethenyl ester (5.1 g, 18.4 mmol, hydrochloric acid (5 ml), andisopropyl alcohol (50 ml) was heated at reflux for 3.5 hours. At the endof the reaction, the solvent was reduced to about 30 ml on a rotaryevaporator and the mixture was cooled to 0° C. for 2 hours. The crystalswere collected by filtration and rinsed with cold isopropyl alcohol. The6-fluoro-3-(3-pyrrolidinyl)-1,2-benzisoxazole hydrochloride productweighed 3.09 g (69%), m.p.=225-227° C.

ANALYSIS: Calculated for C₁₁ H₁₁ FN₂ O.HCl: 54.44% C 4.99% H 11.54% N;Found: 54.35% C 4.99% H 11.38% N

EXAMPLE 1111-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-hydroxy-phenyl]ethanone

A mixture ofN-[3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propyl-6-acetyl-2-benzoxazolinone(6.0 g, 14 mmol) and 10% aqueous sodium hydroxide (50 ml) was stirredand refluxed for 40 minutes. Water was added and the reaction was madeacidic with 5% hydrochloric acid. Saturated Na₂ CO₃ was added untileffervescence ceased. The aqueous mixture was extracted withdichloromethane. The dichloromethane extract was washed (water), dried(K₂ CO₃) and concentrated to afford 2.6 g of a tacky solid. The crudesolid was treated with saturated NaHCO₃, and extracted intodichloromethane. The dichloromethane was washed (brine and then water),and dried (MgSO₄). The organic extract was then concentrated to yield2.4 g of a brown solid, which was combined with another sample to yield5.0 g. This sample was flash chromatographed on silica. A small sample(0.25 g) was recrystallized from toluene to yield1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamino]-3-hydroxyphenyl]ethanoneas a brownish solid, 0.15 g, m.p.=150-152° C.

ANALYSIS: Calculated for C₂₃ H₂₆ FN₃ O₃ : 67.14% C 6.37% H 10.21% N;Found: 67.54% C 6.58% H 9.95% N

EXAMPLE 112 1-[3-Acetylamino-4-(3-chloropropoxy)phenyl]ethanone

A stirred mixture of 1-[3-acetylamino-4-hydroxyphenyl]-ethanone (7.7 g,40 mmol), K₂ CO₃ (5.7 g), 3-chloro-1-bromopropane (8.9 g, 56 mmol), andacetone (100 ml) was refluxed for 16 hours. The reaction was allowed tocool to ambient temperature, and filtered. Concentration of the filtrateyielded 8.5 g of a white solid. The solid was recrystallized fromtoluene and then from ethanol to afford 6.5 g of an off-white solid. A3.3 g sample of this material was flash chromatographed on silica gel.Concentration of the appropriate fractions afforded 2.8 g of a whitesolid. The solid was recrystallized from toluene and then fromethanol-water to yield 2.2 g (51%) of1-[3-acetylamino-4-(3-chloropropoxy)phenyl]ethanone as a white solid,m.p.=124-126° C.

ANALYSIS: Calculated for C₁₃ H₁₆ ClNO₃ : 57.89% C 5.98% H 5.19% N;Found: 57.08% C 5.85% H 5.13% N

EXAMPLE 113 N-[2-(3-hydroxypropoxy)phenyl]acetamide

A stirred mixture of 2-hydroxyphenylacetamide (10.0 g, 66 mmol), K₂ CO₃(6.9 g), 3-bromopropanol (12.8 g, 12 mmol), and acetone (250 ml) wasrefluxed for 16 hours. The reaction mixture was allowed to cool, andthen it was filtered. The filtrate was concentrated to yield 19.0 g of athick, brown oil. The oil was distilled with a Kugelrohr apparatus and11.2 g (82%) of a viscous, orange oil was collected. The oil solidifiedupon standing. An analytical sample was obtained by recrystallizationfrom ethyl acetate to afford the alcohol as an off-white solid,m.p.=78-80° C.

ANALYSIS: Calculated for C₁₁ H₁₅ NO₃ : 63.14% C 7.23% H 6.69% N; Found:63.10% C 7.32% H 6.64% N

EXAMPLE 114 4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butylbromide

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (12 g, 55mmol), K₂ CO₃ (13 g) and 1,4-dibromobutane (20 g, 9.3 mmol, 1.7 eq) inacetonitrile (300 ml) was stirred at room temperature overnight. Theinorganic material was filtered. The solution was concentrated to ˜80ml, when crystals crashed out. The product was filtered to yield 14.16 g(73%), m.p.=243-245° C.

ANALYSIS: Calculated for C₁₆ H₂₀ BrFN₂ O: 54.09% C 5.67% H 7.89% N;Found: 54.13% C 5.52% H 7.83% N

EXAMPLE 115 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylacetate fumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6mmol), K₂ CO₃ (3.5 g, 25 mmol), 2-bromoethyl acetate (4 g, 26.5 mmol) inacetonitrile (50 ml) was heated at reflux for 4 hours. After cooling toroom temperature, the inorganic salts were filtered and washed with DCM(dichloromethane 50 ml). The organic solvent was removed on a rotaryevaporator to give an oil. The oily product was purified on a flashchromatography column (60 g of SiO₂ ; eluted with MeOH 2%-4% in DCM).The pure product thus obtained weighed 4.43 g. This oil was dissolved inethanol and treated with a solution of fumaric acid (1.2 g) in ethanol.The salt crystallized out at room temperature to yield 3.44 g (57%),m.p.=154-155° C.

ANALYSIS: Calculated for C₁₆ H₁₉ FN₂ O₃.C₄ H₄ O₄ : 56.86% C 5.49% H6.63% N; Found: 56.75% C 5.41% H 6.54% N

EXAMPLE 116N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]morpholine

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6mmol), 2-chloroethyl morpholine hydrochloride (4.46 g, 29.7 mmol) and K₂CO₃ (7.3 g, 2.2 eq) in acetonitrile (60 ml) was heated at reflux for 24hours. The crude mixture was diluted with DCM and filtered. The solventwas concentrated to an oil (˜7.1 g). Purification on a silica gel column(55 g, SiO₂, eluted with MeOH:DCM) yielded a solid product weighing 4 g.Recrystallization from hot ethanol yielded 2.1 g (48%), m.p.=131-132° C.

ANALYSIS: Calculated for C₁₈ H₂₄ FN₃ O₂ : 64.84% C 7.26% H 12.60% N;Found: 64.80% C 7.09% H 12.77% N

EXAMPLE 117N-[2-[4-(6Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimide

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.15 g, 23.4mmol), K₂ CO₃ (4.2 g, 30.4 mmol) and 2-bromoethyl phthalimide (7.13 g,28 mmol) in acetonitrile (250 ml) was heated at reflux for 3.5 hours.The solids and solvent were removed. The residue was purified by flashchromatography (SiO₂, 110 g, eluted with 2-4% CH₃ OH:DCM). The productthus obtained weighed 7.8 g (84%). Part of the material wasrecrystallized to give 2.35 g of off white crystals, m.p.=148-149° C.

ANALYSIS: Calculated for C₂₂ H₂₀ FN₃ O₃ : 67.17% C 5.12% H 10.68% N;Found: 67.01% C 5.20% H 10.76% N

(A)N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimidehydrochloride

To a solution of 8.0 g ofN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimidein dichloromethane/ethanol (150 ml) was added 1M-HCl in ether. The saltcrystallized out rapidly. It was filtered off, washed with ethanol anddried to afford 8.15 g with m.p.=257-259° C., dec. Recrystallizationprovided 7.20 g of pure white salt, with m.p. unchanged.

ANALYSIS: Calculated for :C₂₂ H₂₀ FN₃ O₃.HCl 61.47% C 4.92% H 9.77% N;Found: 61.12% C 5.21% H 9.58% N

EXAMPLE 118 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylmethyl ether fumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.75 g, 17mmol), K₂ CO₃ (3 g, 21.7 mmol), bromoethyl methyl ether (2.84 g, 20.4mmol) in acetonitrile (150 ml) was heated at reflux for 3.5 hours. Thereaction was cooled. The inorganics were filtered and rinsed with DCM.The organic solution was concentrated down to an oil (7 g). Purificationon a flash chromatography column (SiO₂, 45 g; eluted with methanol/DCM)gave a light yellow oil as product (4 g, 87%). This oil was dissolvedinto ethanol and treated with a solution of fumaric acid (1.67 g) inethanol (20 ml). White crystals (5.15 g) were collected, m.p.=157-158°C.

ANALYSIS: Calculated for C₁₅ H₁₉ FN₂ O₂.C₄ H₄ O₄ : 57.86% C 5.88% H7.10% N; Found: 57.53% C 5.94% H 6.94% N

EXAMPLE 119 4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butylacetate fumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (9.5 g, 41mmol), K₂ CO₃ (7.2 g, 51 mmol), and 4-bromobutyl acetate (10 g, 51 mmol)in acetonitrile (200 ml) was heated at reflux for 3.5 hours. At the endof the reaction, the solution was cooled and filtered. The inorganicsalt was washed with DCM (50 ml). The organic solvent was removed. Theresidue was purified on a flash chromatography column (packed withSorbsil C30 silica gel, 100 g, eluted with DCM, 1 liter, increasingmethanol from 2 to 4%, 2.51). The material thus purified weighed 12.92 g(89%). A small sample (1.67 g) was dissolved in ethanol and treated with1 equivalent of fumaric acid (580 mg) in ethanol to yield whitecrystals: 1.8 g, m.p.=142-143° C.

ANALYSIS: Calculated for C₁₈ H₂₃ FN₂ O₃.C₄ H₄ O₄ : 58.66% C 6.04% H6.22% N; Found: 58.56% C 6.02% H 6.13% N

EXAMPLE 120 4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanolfumarate

A mixture of 4-[4(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butylacetate (11.5 g, 34.4 mmol), 15% NaOH (100 ml) and ethanol (100 ml) washeated at reflux for 4 hours. After cooling to room temperature, thebase was neutralized with HCl to pH=7. The solution was concentrateddown to a small volume (˜50 ml), then extracted with DCM. The DCMsolution was washed with brine and dried over MgSO₄. The solvent wasconcentrated to give ˜10 g of crude oil. Purification by flashchromatography (Sorbsil C-30, 100 g, eluted with MeOH:DCM, 3 liters)yielded 9.8 g of white solid. The sample for testing was prepared bytreatment of the free base (2.0 g) with fumaric acid (780 mg. 1.0 eq) inethanol. The crystals were collected and dried: 1.5 g, m.p.=131-132° C.

ANALYSIS: Calculated for C₁₆ H₂₁ FN₂ O₂.C₄ H₄ O₄ : 58.82% C 6.17% H6.86% N; Found: 58.81% C 6.37% H 6.66% N

EXAMPLE 121 4-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyldecanoate fumarate

To a solution of4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (2.0 g, 6.84mmol), triethylamine (1,0 g, 10 mmol) in DCM (70 ml) decanoyl chloride(1.7 g, 8.9 mmol) was added dropwise at room temperature. The mixturewas stirred for 1 hour., then was concentrated to a crude solid. Thesolid was extracted into ethyl acetate, and the insoluble salts werefiltered. The solvents were removed. The crude product was purified byflash chromatography (Sorbsil C-30, 30 g, eluted with a mixture of MeOHin DCM). The oil thus obtained (2.5 g, 81%) was converted to a fumaratesalt with fumaric acid (650 mg, 1.0 eq) in ethanol. Crystals werecollected: 1.48 g, m.p.=109-110° C.

ANALYSIS: Calculated for C₂₆ H₃₉ FN₂ O₃.C₄ H₄ O₄ : 64.04% C 7.70% H4.98% N; Found: 64.30% C 7.86% H 4.78% N

EXAMPLE 122 3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyldecanoate fumarate

To a solution3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propanol (1.81 g,6.5 mmol) triethylamine (0.9 g, 9.0 mmol) in DCM (45 ml) was addeddecanoyl chloride (1.5 g, 7.8 mmol) dropwise at room temperature. Themixture was stirred for 20 minutes, then concentrated down to a crudesolid. The solid was extracted into EtOAc (20 ml), and the insolublesalts were filtered. The EtOAc was removed. The crude oil was purifiedby flash choursomatography (Sorbsil C-30, 30 g; eluted with MeOH:DCM).The oil thus obtained (2.54 g, 90%) was converted to a fumarate saltwith fumaric acid (670 mg) in ethanol. The crystals collected weighed1.61 g, m.p.=100-102° C.

ANALYSIS: Calculated for C₂₅ H₂₇ FN₂ O₃.C₄ H₄ O₄ : 63.52% C 7.54% H5.11% N; Found: 63.63% C 7.74% H 5.03% N

EXAMPLE 123N,N-Diethyl-4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butylcarbamate fumarate

To a mixture of4-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]butanol (1.55 g, 5.3mmol) potassium t-butoxide (750 mg, 6.7 mmol) in THF (100 ml),diethylcarbamyl chloride (900 mg, 6.63 mmol) was added dropwise at roomtemperature. The mixture was stirred for 2 hours, then the solvent wasremoved. The residue was extracted into DCM. The DCM solution was washedwith brine and dried over MgSO₄. The solution was concentrated. Theproduct was purified on a flash chromatography column (SiO₂, 14 g,eluted with 2% MeOH in DCM), to yield 1.84 g of oil. This oil wasdissolved into ethanol (˜5 ml) and treated with a solution of fumaricacid (850 mg, 1.0 eq) in ethanol. Crystallization was induced with asmall volume of isopropyl ether to produce 2.09 g, m.p.=152-153° C.

ANALYSIS: Calculated for C₂₁ H₃₀ FN₃ O₃.C₄ H₄ O₄ : 59.16% C 6.75% H8.28% N; Found: 59.17% C 6.84% H 8.16% N

EXAMPLE 124N-Methyl4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butylcarbamate fumarate

To a mixture of4-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]butanol (1.84 g, 6.3mmol), K₂ CO₃ (850 mg) in chloroform, methyl isocyanate (448 mg, 7.7mmol and 360 mg, 6.2 mmol) was added dropwise in two portions. Themixture was filtered and concentrated to a crude oil. Purification wasdone on a flash chromatography column (SiO₂, 11 g, eluted with 2% CH₃ OHin DCM) to yield a light yellow oil (2.05 g, 93%). This oil wasdissolved into ethanol and treated with a solution of fumaric acid (800mg, 1.0 eq). Crystallization was induced with drops of isopropyl ether.Weight: 1.36 g, m.p.=96-98° C.

ANALYSIS: Calculated for C₁₈ H₂₄ FN₃ O₃.C₄ H₄ O₄ : 56.76% C 6.06% H9.02% N; Found: 56.27% C 6.03% H 8.86% N

EXAMPLE 1252-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,3-dioxanefumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9.1mmol), K₂ CO₃ (1.5 g, 10.9 mmol) and bromoethyl-1,3-dioxane (2.1 g, 10.7mmol) in acetonitrile (50 ml) was heated at reflux for 3 hours. At theend, the insolubles were filtered and rinsed with DCM and the filtratewas evaporated down. The crude mixture was purified by flashchromatography over a silica gel column (Sorbsil C-30, 25 g; eluted withDCM and MeOH (1-3%) in DCM). The fractions containing the pure productwere combined and concentrated to give 3.13 g of oil. The oil wastreated with a fumaric acid (1.0 g) ethanol solution. The crystals werecollected: 3.98 g (77%), m.p.=161-162° C.

ANALYSIS: Calculated for C₁₈ H₂₃ FN₂ O₃.C₄ H₄ O₄ : 58.66% C 6.04% H.6.22% N; Found: 58.69% C 5.96% H 6.20% N

EXAMPLE 126 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl-1-piperidinyl]ethanolhemifumarate.

(A) 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl acetate

2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl acetate wasprepared according to Example 115.

(B) 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl-1-piperidinyl]ethanolhemifurmarate

2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl acetate (10.58g, 34.6 mmol), 15% NaOH (100 ml) and ethanol (100 ml) was heated atreflux for 4 hours. The solution was cooled (˜5° C.) and neutralizedwith HCl to pH˜7. The ethanol was removed under reduced pressure. Theaqueous solution was basified with NaHCO₃ and extracted with DCM (2×200ml). The DCM solution was washed with brine and dried over MgSO₄ andevaporated to give a white solid: 6.88 g (75%). A sample (2.03 g) wasdissolved in ethanol and treated with fumaric acid (660 mg, 1.0 eq).Crystallization was induced with drops of isopropyl ether to yieldoff-white crystals: 1.43 g, m.p.=159-161° C.

ANALYSIS: Calculated for C₁₄ H₁₇ FN₂ O₂.0.5C₄ H₄ O₄ : 59.62% C 5.94% H8.69% N; Found: 59.55% C 5.95% H 8.53% N

EXAMPLE 127 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyldecanoate fumarate

A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylalcohol (1.6 g, 5 mmol) and triethylamine (800 mg, 8 mmol) in chloroform(100 ml) was treated with decanoyl chloride (1.3 g, 7.2 mmol) dropwiseat room temperature. The mixture was stirred for 4 hours. The solventwas removed to leave a crude solid. The solid was dissolved into a smallamount of DCM (15 ml), then was filtered. The solution was concentrated.

The purification was done by flash chromatography over a silica gelcolumn (Sorbsil C-30, 30 g; eluted with MeOH:DCM). The purified oil(2.45 g, 95%) was treated with a fumaric acid (660 mg, 1.0 eq)/ethanolsolution (15 ml). Crystallization was induced by adding drops of ether;yield: 1.97 g, m.p.=109-110° C.

ANALYSIS: Calculated for C₂₄ H₃₅ FN₂ O₃.C₄ H₄ O₄ : 62.90% C 7.35% H5.24% N; Found: 62.93% C 7.30% H 5.14% N

EXAMPLE 128N,N-Diethyl-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethylcarbamate fumarate

To a mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]ethanol (1.6 g, 6mmol) and potassium t-butoxide (850 mg, 7.6 mmol) in THF (100 ml)diethyl carbamyl chloride (1.03 g, 7.5 mmol) was added dropwise at roomtemperature. The mixture was stirred for 4 hours. The reaction mixturewas concentrated to a crude solid. The solid was dissolved in DCM andpurified on a flash chromatography column (Sorbsil C-30, 27 g; elutedwith a MeOH:DCM mixture). The product thus purified as a light oil (2.2g, 91%) was dissolved into ethanol and treated with a fumaric acid (690mg, 1.0 eq)/ethanol solution (15 ml). Crystallization on cooling yielded2.15 g of white crystals, m.p.=133-135° C.

ANALYSIS: Calculated for C₁₉ H₂₆ FN₃ O₃.C₄ H₄ O₄ : 57.61% C 6.31% H8.76% N; Found: 57.49% C 6.25% H 8.54% N

EXAMPLE 1292-[4-[(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]aminehemifumarate

(A) N-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylphthalimide

N-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl phthalimidewas prepared according to Example 117.

(B) 2-[4-[(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]aminehemifumarate

A mixture of 2-[4(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylphthalimide (4.6 g, 11.7 mmol) and hydrazine monohydrate (1.17 g, 23.4mmol) in methanol (50 ml) was heated at reflux overnight. At the end ofthe reaction, methanol was removed to leave a crude solid. This wasstirred with water (150 ml) and acidified with HCl to pH=2. Theinsolubles were filtered. The aqueous solution was basified with 50%NaOH then extracted with DCM (2×250 ml). The DCM solution was washedwith brine and dried over MgSO₄. The solvent was removed to produce acolorless oil: 2.12 g. This oil was treated with a solution of fumaricacid (935 mg, 1.0 eq) in ethanol. The salt crystallized out: 0.99 g,m.p.=203-205° C. A second crop of 0.73 g (m.p.=198-200° C.) wascollected later.

ANALYSIS: Calculated for C₁₄ H₁₈ FN₃ O.0.5C₄ H₄ O₄ : 59.80% C 6.27% H13.07% N; Found: 59.51% C 6.35% H 13.31% N

EXAMPLE 130 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyldecanamide fumarate

To a mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (1.49 g,5.5 mmol) and triethylamine (1.0 g, 10 mmol) in chloroform (50 ml)decanoyl chloride (1.26 g, 6.6 mmol) was added at room temperature. Themixture was stirred for 3 hours at room temperature. The solvent wasstripped down to a crude mixture. This crude mixture was purified byflash chromatography over a silica gel column (SiO₂, 20 g; eluted with asolution of MeOH (0-3%) in DCM). The fractions containing the pureproduct were pooled and concentrated to give 2.3 g of oil. This oil wasconverted to a fumarate salt by treatment with fumaric acid (655 mg) inethanol. The ethanol was concentrated down to a small volume and 3volumes of isopropyl ether was added. This mixture was stirred overnightto cause crystallization. The solids were collected, weighed: 1.83 g(60.5%), m.p.=108-110° C.

ANALYSIS: Calculated for C₂₄ H₃₆ FN₃ O₂.C₄ H₄ O₄ : 63.02% C 7.56% H7.87% N; Found: 62.42% C 7.58% H 7.66% N

EXAMPLE 131 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylacetamide fumarate

A mixture of2-[4(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.56 g,9.7 mmol) and triethylamine (1.45 g, 14.5 mmol) in DCM (50 ml) wastreated with dropwise addition of acetyl chloride (1.0 g, 12.7 mmol) atroom temperature. The mixture was stirred for 4 hours at roomtemperature. The reaction mixture was diluted with DCM and washed withbrine. The organic solution was dried over MgSO₄ and concentrated to acrude oil. The crude oil was purified by flash chromatography over asilica gel column (SiO₂, 20 g; eluted with (0-2%) CH₃ OH in DCM). Thepure product thus obtained weighed 1.36 g (46%). It was converted to afumarate salt by treatment with fumaric acid (517 mg) in ethanol.Recrystallization from ethanol gave white crystals; weight: 1.53 g,m.p.=132-133° C.

ANALYSIS: Calculated for C₁₆ H₂₀ FN₃ O₂.C₄ H₄ O₄ : 57.00% C 5.74% H9.97% N; Found: 57.05% C 5.85% H 9.95% N

EXAMPLE 1322-[[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amino]ethylacetate fumarate

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.0 g,7.6 mmol), K₂ CO₃ (1.38 g, 10 mmol) and bromoethyl acetate (1.40 g, 8.3mmol) in acetonitrile (50 ml) was heated at reflux for 4 hours. At theend, the insolubles were filtered off and rinsed with DCM. The solventwas evaporated down. The crude mixture was purified by flashchromatography over a silica gel column (Sorbsil C-30, 30 g; eluted with2% CH₃ OH in DCM, 800 ml). The oil (1.15 g) thus obtained was treatedwith a solution of fumaric acid (358 mg) in ethanol. Crystallization wasinduced by adding drops of ethyl ether, yield: 1.09 g, m.p.=116-118° C.

ANALYSIS: Calculated for C₁₈ H₂₄ FN₃ O₃.C₄ H₄ O₄ : 56.77% C 6.06% H9.03% N; Found: 56.32% C 5.97% H 8.94% N

EXAMPLE 133 Methyl2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl carbamatefumarate

A mixture of2-[4[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.0 g,7.6 mmol) and triethylamine (1.0 g, 10 mmol) in DCM (50 ml) was treatedwith methyl chloroformate (860 mg, 9.12 mmol) dropwise at roomtemperature. The mixture was stirred for 1 hour. The reaction mixturewas diluted with DCM and washed with brine. The organic solution wasdried over MgSO₄ and concentrated to a crude oil. The purification wasdone by flash chromatography over a silica gel column (28 g of SorbsilC-30, eluted with DCM and MeOH/DCM). The pure oil thus obtained weighed2.34 g. It was converted to a fumarate salt by treatment with fumaricacid (840 mg, 1.0 eq) in ethanol. Crystallization was induced by addingdrops of isopropyl ether, yield: 2.31 g, m.p.=163-165° C.

ANALYSIS: Calculated for C₁₆ H₂₀ FN₃ O₃.C₄ H₄ O₄ : 54.92% C 5.53% H9.61% N; Found: 54.49% C 5.45% H 9.24% N

EXAMPLE 134Z-2-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]hexahydro-1H-isoindole-1,3-dionefumarate

A mixture of1-(2-aminoethyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.77 g,14.3 mmol) and cis-1,2-cyclohexane-dicarboxylic anhydride (2.82 g, 18.2mmol, 1.25 eq) in dry pyridine (50 ml) was heated at 65° C. for 48hours. The dark brown solution was concentrated to dryness on a rotaryevaporator. The crude residue was purified twice by flash chromatographyover a silica gel column (SiO₂, 45 g and 50 g, eluted with DCM and 1%CH₃ OH in DCM). The pure product thus obtained 2.35 g (41%), wasconverted to the fumarate salt by treatment with fumaric acid (660 mg)in ethanol. The crystals after two recrystallizations weighed 1.37 g,m.p.=172-173° C.

ANALYSIS: Calculated for C₂₂ H₂₆ FN₃ O₃.C₄ H₄ O₄ : 60.57% C 5.87% H8.15% N; Found: 60.40% C 5.55% H 7.82% N

EXAMPLE 135(S)-(+)-3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propanolfurmarate

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (7.2 g, 32.7mmol), (S)-(+)-3-bromo-2-methyl-1-propanol (5.0 g, 32.6 mmol), K₂ CO₃(7.19 g, 52 mmol) in acetonitrile (250 ml) was heated at refluxovernight. The insolubles were filtered off. The solvent was removed atreduced pressure and the crude residue was purified by silica gelchromatography (SiO₂, 84 g, eluted with 21 of 1% CH₃ OH in DCM) to givethe target compound as an off-white solid (8.83 g, 94%). A sample of 1.7g was converted to the fumarate salt by treatment with fumaric acid (710mg) in ethanol. Recrystallization from ethanol yielded 1.74 g of whitecrystals, m.p.=119-121° C.

ANALYSIS: Calculated for C₂₀ H₂₅ FN₂ O₆ : 58.82% C 6.17% H 6.86% N;Found: 58.81% C 6.24% H 6.76% N

EXAMPLE 1364-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-[3-(1-piperidinyl)propyl]piperidinedifumarate

A mixture of 4-(6fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6mmol), N-(3-chloropropyl)piperidine hydrochloride (4.05 g, 20.4 mmol),K₂ CO₃ (6 g, 43.4 mmol), tetrabutylammonium hydrogen sulfate (phasetransfer catalyst, 2.3 g) in acetonitrile (100 ml) and water (15 ml) washeated at reflux for 16 hours. The mixture was washed with brine and thelayers were separated. The organic solution was concentrated. The crudeproduct (6.4 g) was purified by flash chromatography over a silica gelcolumn (55 g, sorbsil C-30; eluted with 2% CH₃ OH:0.5% DEA in DCM, 1.4l). The oil thus purified (4.5 g) was treated with fumaric acid (1.6 g)in ethanol. The solid was collected: weight 3.1 g, m.p.178-181° C.Recrystallization from ethanol yielded 2.28 g of white crystals,m.p.=190-192° C.

ANALYSIS: Calculated for C₂₀ H₂₄ FN₃ O₂.C₄ H₄ O₄ : 58.22% C 6.28% H7.27% N; Found: 58.39% C 6.36% H 7.34% N

EXAMPLE 1371-(3-Dimethylaminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3yl)piperidinedifumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.05 g, 13.8mmol), 3-dimethylaminopropyl chloride hydrochloride (3.4 g, 21 mmol), K₂CO₃ (6.2 g, 45 mmol), tetrabutylammonium hydrogen sulfate (phasetransfer catalyst, 1.5 g) in acetonitrile (100 ml) and water (50 ml) washeated at 60° C. overnight. The aqueous phase was separated, andacetonitrile was removed at reduced pressure. The residue was extractedinto DCM. The organic solution was washed with H₂ O and brine, thendried with MgSO₄. The solvent was removed and the crude product (4.3 g)was treated with fumaric acid (1.58 g, 1.0 eq) in dilute ethanol. Thecrystals were collected (2.53 g), m.p.=192-194° C. Recrystallizationfrom ethanol yielded 2.08 g of white crystals, mp=194-195° C.

ANALYSIS: Calculated for C₁₇ H₂₄ FN₃ O₂.C₄ H₄ O₄ : 55.86% C 6.00% H7.82% N; Found: 56.11% C 5.94% H 7.86% N

EXAMPLE 138(R)-(-)-3-[4-(6Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propanolfumarate

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (14.5 g, 65mmol), K₂ CO₃ (10 g, 72 mmol). (R)-(-)-3-bromo-2-methyl-1-propanol (10g, 65.3 mmol), tetrabutylammonium hydrogen sulfate (1.27 g, phasetransfer catalyst) in acetonitrile (300 ml) and H₂ O (5 ml) was heatedat reflux for 6 hours. The mixture was cooled and the solvent wasremoved on rotary evaporator. The residue was extracted into methylenechloride (DCM), and the insolubles were filtered. After concentration ofthe extract, the crude product was purified by flash chromatography overa silica gel column (SiO₂, 150 g; eluted with DCM, 1 l; 2% CH₃ OH inDCM, 1.6 l). The material thus purified weighed 17 g (89%). The samplefor testing was prepared by treatment of a sample (2.28 g) with fumaricacid (953 mg) in ethanol. The crystals formed slowly upon addition ofisopropyl ether. These were collected and dried: weight 1.84 g,m.p.=114-115° C.

ANALYSIS: Calculated for C₁₆ H₂₁ FN₂ O₂.C₄ H₄ O₄ : 58.82% C 6.17% H6.86% N; Found: 58.48% C 6.08% H 6.57% N

EXAMPLE 1393-[1-[3-[4-(1-Methoxyethyl)-2-hydroxyphenoxyl]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (5.7 g, 26.0mmol), 4-(3-chloropropoxy)-3-hydroxy-α-methylbenzenemethanol (6.0 g,26.0 mmol), NaHCO₃ (2.4 g, 28.6 mmol), KI(200 mg) and CH₃ CN (150 ml)was stirred at reflux under N₂ for 17 hours. A TLC showed a trace of thealkylating side chain, therefore additional6-fluoro-3(4-piperidinyl)-1,2-benzisoxazole (0.6 g, 2.7 mmol) and NaHCO₃(0.22 g, 2.6 mmol) was added and the reaction was refluxed 3 hourslonger. The cooled reaction was concentrated and the residue waspartitioned between EtOAc and H₂ O. The EtOAc extract was washed with H₂O then brine and after drying with MgSO₄ the extract was concentrated toyield 11.9 g of a beige oil. The sample was purified by preparative HPLC(Water's Associates Prep LC/System 500 utilizing 2 silica gel columnsand eluting with 5% MeOH-CH₂ Cl₂). Concentration of later fractionsafforded 4.2 g of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzenemethanol.Concentration of earlier fractions gave 4.0 g of a mixture of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzenemethanoland3-[1-[3-[4-(1-methoxyethyl)-2-hydroxy-phenoxyl]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole(the latter was apparently formed by the reaction of the former withMeOH on silica gel). The mixture was dissolved in anhydrous Et₂ O (330ml) and anhydrous MeOH (100 ml) and ethereal HCl was added. Afterstirring 1.5 hours, anhydrous Et₂ O was added and the resultant solidwas collected and dried to yield 2.9 g of a mixture of the respectiveHCl salts. The solid was suspended in H₂ O and was basified with NH₄ OH.The aqueous mixture was extracted with CH₂ Cl₂ and the extract waswashed with H₂ O, dried with MgSO₄ and concentrated to yield 2.7 g of alight beige oil. The oil was purified by preparative HPLC (Water'sAssociates Prep LC/System 500 using 2 silica gel columns and 3% MeOH-CH₂Cl₂ as eluent). Concentration of later fractions yielded 0.5 g of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-hydrox-α-methylbenzenemethanol.Concentration of earlier fractions gave an oil that solidified uponstanding. The product was triturated with heptane and filtered to yield1.2 g of a white powder. The compound was recrystallized from EtOH toprovide 1.1 g (10%) of3-[1-[3-[4-(1-methoxyethyl)-2-hydroxyphenoxyl]propyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazoleas clean white crystals m.p.=98-100° C.

ANALYSIS: Calculated for C₂₄ H₂₉ FN₂ O₄ : 67.27% C 6.82% H 6.54% N;Found: 67.18% C 6.84% H 6.54% N

EXAMPLE 1406-Fluoro-3-[1-[3-[(1H-indol-5-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.6 g, 11.8mmol), K₂ CO₃ (1.6 g, 11.6 mmol), KI (200 mg), 5-(3chloropropoxy)indole(2.2 g, 10.5 mmol) and CH₃ CN (100 ml) was stirred at reflux under N₂for 18 hours. The cooled reaction was poured into H₂ O and the aqueousmixture was extracted with EtOAc. The EtOAc extract was washed 2 timeswith H₂ O, 2 times with brine and after drying with MgSO₄ the solventwas removed in vacuo to yield 5.1 g of a dark oil. The oil was purifiedby preparative HPLC (Water's Associates Prep LC/System 500, using 2silica gel columns and 4% MeOH-CH₂ Cl₂ as eluent) to afford 2.65 g (65%)of a beige solid. Recrystallization from ethanol gave 2.2 g (54%) of abeige powder, m.p.=118-121° C.

ANALYSIS: Calculated for C₂₃ H₂₄ FN₃ O₂ : 70.21% C 6.15% H 10.68% N;Found: 69.80% C 6.21% H 10.78% N

EXAMPLE 1416-Fluoro-3-[1-[3[(isoquinol-5-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazolesesquifumarate

A stirred mixture of 6-fluoro-3(4-piperidinyl)-1,2-benzisoxazole (2.8 g,13 mmol), 5-(3-chloropropoxy)isoquinoline (2.8 g, 13 mmol), K₂ CO₃ (1.7g) and CH₃ CN (50 ml) was refluxed for 16 hours. The reaction wasfiltered and the filtrate was concentrated to an oil. The filter cakewas treated with H₂ O, and the aqueous suspension was extracted with CH₂Cl₂. The filtrate was also extracted with CH₂ Cl₂, and the extracts werecombined, washed (H₂ O), dried (K₂ CO₃) and concentrated to yield 5.4 gof a brown oil. The oil was purified by HPLC on silica gel columns,eluting with CH₂ Cl₂ /MeOH (5%), to afford 2.3 g of a yellow oil. Theoil was dissolved in EtOAc and fumaric acid (0.66 g, 1 eq) was added.The mixture was refluxed briefly, and then stirred at ambienttemperature for 16 hours. The resulting white solid was collected toafford 2.2 g of the fumarate salt. The compound was recrystallized fromDMF to yield 1.4 g (18.6%) of the isoquinoline as a sesquifumarate,m.p.=213-215° C.

ANALYSIS: Calculated for C₃₀ H₃₀ FN₃ O₈ : 62.17% C 5.22% H 7.25% N;Found: 62.01% C 5.11% H 7.28% N

EXAMPLE 1426-Fluoro-3-[1-[3-[(1-H-indol4-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.5 g, 16mmol), K₂ CO₃ (2.2 g, 16 mmol), KI (200 mg), 4-(3-chloropropoxy)indole(3.0 g, 14 mmol) and CH₃ CN (100 ml) was stirred at reflux under N₂ for7 hours and then at ambient temperature for 68 hours. Reflux was resumedfor an additional 6 hours whereupon a TLC revealed incomplete reaction.K₂ CO₃ (0.5 g, 4 mmol) was added and the reaction was stirred at refluxfor 17 hours. The cooled reaction was poured into H₂ O and the aqueousmixture was extracted with EtOAc. The organic extract was washed with H₂O and saturated NaCl and after drying over MgSO₄ the solvent was removedto afford 5.7 g of a beige solid. The product was purified bypreparative HPLC (Water's Associates Prep LC/System 500 using 2 silicagel columns and 4% MeOH-CH₂ Cl₂ as eluent) to yield 3.4 g (61%) of abeige solid. Two consecutive recrystallizations from EtOH provided 2.3 g(41%) of a white powder, m.p.=129-131° C.

ANALYSIS: Calculated for C₂₃ H₂₄ FN₃ O₂ : 70.21% C 6.15% H 10.68% N;Found: 69.90% C 6.15% H 10.65% N

EXAMPLE 1436-Fluoro-3-[1-[3-[(6-methoxy-1H-indol-5-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazolehemifumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 14mmol), 5-(3-chloropropoxy)-6-methoxyindole (3.0 g, 13 mmol), K₂ CO₃ (2.1g, 14 mmol), KI (200 mg) and CH₃ CN (150 ml) was stirred at reflux underN₂ for 48 hours. The cooled reaction was poured into H₂ O and theaqueous mixture was extracted with EtOAc. The EtOAc extract was washedwith H₂ O and brine and was dried with MgSO₄. Removal of the solvent invacuo gave 5.6 g of a dark oil. The oil was purified by preparative HPLC(Water's Associates Prep LC/System 500 using 2 silica gel columns and 2%Et₂ NH-EtOAC as eluent) to yield 2.5 g (47%) of a beige solid.Recrystallization from EtOH afforded 2.0 g of an off white powder. A 1.8g (4 mmol) sample was dissolved in warm EtOAc and fumaric acid (0.5 g, 4mmol) was added. The reaction was stirred at ca 40° C. for 30 minutesand was then allowed to gradually cool to ambient temperature. Theresultant hemifumarate salt was collected and dried to yield 2.0 g. Theproduct was recrystallized from EtOH to provide 1.5 g (25%) of a lightbeige powder m.p.=186-188° C.

ANALYSIS: Calculated for C₂₆ H₂₈ FN₃ O₅ : 64.84% C 5.87% H 8.73% N;Found: 64.22% C 5.85% H 8.55% N

EXAMPLE 1441-[4-[3-[4-(6-Fluoro1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (2.4 g, 10.1mmol), 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone (2.5 g, 11.1mmol), NaHCO₃, (0.94 g, 11.1 mmol), KI (100 mg) and CH₃ CN (100 ml) wasstirred at reflux under N₂ for 65 hours. The cooled reaction was pouredinto H₂ O and the aqueous mixture was extracted with EtOAc. The EtOAcextract was washed with H₂ O (1×) and brine (3×) and after drying withMgSO₄ the solvent was evaporated to give 4.2 g of a dark solid. Threeconsecutive recrystallizations from EtOH provided 2.1 g (48%) ofglittery beige crystals m.p.=135-137° C.

ANALYSIS: Calculated for C₂₃ H₂₅ FN₂ O₃ S: 64.47% C 5.88% H 6.54% N;Found: 64.44% C 5.69% H 6.29% N

EXAMPLE 1454-[3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α-methylbenzenemethanol

To a stirred solution of1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone(4.1 g, 9.3 mmol) in 60 ml MeOH-THF (1:1) under N₂ at ambienttemperature, NaBH₄ (0.386 g, 10.2 mmol) was added portionwise. Aftercomplete addition, the reaction was stirred for 3.5 hours and wasconcentrated to yield a white gum. This was triturated with H₂ O (2×)and the aqueous fraction was decanted away. Residual water was removedunder high vacuum to afford 5.0 g of a white powder. The compound wastaken up in boiling toluene and the insolubles were filtered away.Concentration of the toluene filtrate afforded 3.8 g of a beige solid.Purification via preparative HPLC (Water's Associates prep LC/System500, using 2 silica gel columns and 2% Et₂ NH-EtOAc) provided 2.7 g of alight beige solid. The product was recrystallized from EtOAc to afford1.7 g (42%) of a pure white powder, m.p.=113-115° C.

ANALYSIS: Calculated for C₂₄ H₂₉ FN₂ O₃ S: 64.84% C 6.58% H 6.30% N;Found: 64.85% C 6.44% H 6.19% N

EXAMPLE 146(R)-(-)-3-[4-(6Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propylacetate fumarate

To a mixture of(R)-(-)-3-[4-(6fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propanol(3.2 g, 11 mmol), triethylamine (3.2 g, 11 mmol) in DCM (100 ml), acetylchloride (890 mg, 11.3 mmol) was added dropwise at 0° C. The mixture wasstirred at room temperature for 4.5 hours. The solvent was removed on arotary evaporator. The triethylamine HCl salt was filtered off using asmall amount of DCM. The crude product was dissolved in DCM was purifiedby flash chromatography over a silica gel column (SiO₂ 30 g; eluted withDCM and 1% CH₃ OH in DCM). The oil, thus purified, weighed 2.11 g (58%).This oil was treated with a solution of fumaric acid (695 mg, 1.0 eq.)in ethanol to give the fumarate salt. Recrystallization from ethanol andisopropyl ether again yielded white crystals, 2.09 g, m.p.=118-120° C.

ANALYSIS: Calculated for C₁₈ H₂₃ FN₂ O₃.C₄ H₄ O₄ : 58.66% C 6.04% H6.22% N; Found: 58.53% C 5.76% H 8.91% N

EXAMPLE 1471-(R)-(-)-[4-[3-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propoxy]-3-methoxyphenyl]ethanonefumarate

(A)(R)-(-)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propylmethanesulfonate

To a mixture of(R)-(-)-3-[4-(6fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propanol(7.26 g, 24.8 mmol), triethylamine (3 ml, 30 mmol) in methylene chloride(DCM, 120 ml), methanesulfonyl chloride (3.13 g, 27.3 mmol) was addeddropwise at 0° C. The mixture was stirred at room temperature for 1hour., then concentrated down to a crude mixture. Triethylaminehydrochloride salt was removed by filtration with DCM/ether as solvent.The crude oily mixture was purified with a flash chromatography column(SiO₂, 90 g; eluted with DCM). The colorless oil, which is themethanesulfonate ester, weighed 6.48 g (70%), and was used directly inthe following step.

(B)1-(R)-(-)-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylproproxy]-3-metlioxyphenyl]ethanonefumarate

A solution of the above methanesulfonate (6.48 g, 175 mmol) in DMF (5ml) was added in one portion to an aged (hour) cold mixture ofacetovanillone (4.13 g, 24.9 mmol) and sodium hydride (670 mg, 26.5mmol) in DMF (40 ml) at 0° C. The resulting mixture was warmed to ˜50°C. briefly and stirred at room temperature for 16 hours. The mixture wasextracted into DCM (500 ml) and washed twice with water, then brine. Theorganic solution was dried over MgSO₄ and concentrated to an oil. Thiscrude mixture was purified twice by flash chromatography over a silicagel column. The material thus purified weighed 5.37 g. The fumarate saltwas prepared by treatment of purified oil with fumaric acid (1.0 eq.) inethanol and ether. Slightly off-white crystals were collected: 3.76 g(38%), m.p.=141-142° C.

ANALYSIS: Calculated for C₂₅ H₂₉ FN₂ O₄.C₄ H₄ O₄ : 62.58% C 5.98% H5.03% N; Found: 62.52% C 5.75% H 4.96% N

EXAMPLE 1483-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2,2-dimethyl-1-propanolfumarate

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6mmol), K₂ CO₃ (12.5 g, 17.5 mmol), 3-bromo-2,2-dimethyl-1-propanol (3 g,21 mmol, 1.5 eq.), tetra-butylammonium hydrogen sulfate (1 g, phasetransfer catalyst) in water (5 ml) and acetonitrile (150 ml) was heatedat reflux for 43 days. TLC showed a small spot for the expected product.The mixture was diluted with EtOAc (400 ml) and washed with brine. Theorganic solution was dried and concentrated to a dark brown mixture. Thecrude mixture was purified carefully by flash chromatography (SiO₂, 95 gto afford the dried pure product; 260 mg, (6%) as an oil. This oil wasconverted to the fumarate salt by treatment with fumaric acid (98.5 mg,1.0 eq.) in ethanol. Recrystallization from ethanol:ether yielded 210 mgof white crystals, m.p.=144-145° C.

ANALYSIS: Calculated for C₁₇ H₂₃ FN₂ O₂.C₄ H₄ O₄ : 59.70% C 6.44% H6.63% N; Found: 59.52% C 6.38% H 6.52% N

EXAMPLE 1491-(S)-(+)-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propoxy]-3-methoxyphenyl]ethanonefumarate

(A)(S)-(+)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propylmethanesulfonate

To a mixture of(S)-(+)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propanol(8.8 g, 30 mmol), triethylamine (3.2 g, 32 mmol) in dichloromethane(DCM, 150 ml), methanesulfonyl chloride (4 g, 35 mmol) was addeddropwise at 0° C. over 10 minutes. The mixture was stirred at roomtemperature for 1 hour, then concentrated. Triethylamine HCl salt wasfiltered off with a little DCM as solvent. The crude oil was purifiedwith a flash chromatography column (SiO₂, 90 g; eluted with DCM). Thecolorless oil thus purified weighed 5.28 g (47%) was used immediately inthe following step.

(B)1-(S)-(+)-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-proproxy]-3-methoxyphenyl]ethanonefumarate

A solution of(S)-(+)-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-1-propylmethanesulfonate (5.28 g, 14.27 mmol) in dimethylformamide (DMF, 10 ml)was added in one portion to an aged (1 hour) cold mixture ofacetovanillone (3.55 g, 33.1 mmol) and sodium hydride (530 mg, 22 mmol)in DMF (35 ml) at 0° C. under N₂. The reaction was stirred overnight (16hours.) at room temperature. The mixture was diluted with EtOAc andwashed with H₂ O (2 times) and brine. The organic solution was dried andconcentrated to an oil (9.4 g). The crude oil mixture was purified byflash chromatography (SiO₂, 60 g). The oil thus purified weighed 4.3 g,(68%) and was converted to the fumarate salt (fumaric acid, 1.13 g) inethanol. Recrystallization from ethanol gave 1.36 g of white crystals,m.p.=163-165° C.

ANALYSIS: Calculated for C₂₅ H₂₉ FN₂ O₄.C₄ H₄ O₄ : 62.58% C 5.98% H5.03% N; Found: 62.40% C 5.84% H 4.92% N

EXAMPLE 150 2-[4(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylthioacetate fumarate

To a stirred solution of 0° C. of triphenlyphosphine (13.3 g, 50 mmol)in THF (150 ml), diisopropylazodicarboxylate (10.2 ml, 50 mmol) wasadded dropwise. After stirring at 0° C. for 0.5 hour, a solution of6-fluoro-3-[1-(2-hydroxyethyl)-4-piperidinyl]-1,2-benzisoxazole (8.5 g,32 mmol) and thioacetic acid (10.2 ml, 0.14 mol) in DMF (35 ml) wasadded dropwise. The reaction was then stirred at ambient temperature for16 h, and then it was concentrated at 60° C., under vacuum, to yield ared oil. The oil was triturated with H₂ O, and then it was flashchromatographed on silica gel, eluting first with CH₂ Cl₂ and then with10% MeOH-CH₂ Cl₂. The appropriate fractions were concentrated to yield16.5 g of an oil. The oil was triturated with Et₂ O and the solid(reaction by-products) that formed was removed by filtration. Thefiltrate was treated with fumaric acid (4.3 g), and 7.2 g of thefumarate salt of the desired product was obtained as an off white solid.The salt was recrystallized from EtOAc and then twice from EtOH toafford 1.0 g (7.0%) of the thioacetate as an off white solid,m.p.=118-120° C.

EXAMPLE 151N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4,5-dichlorophthalimide

A mixture of2-[4[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.83 g,10.7 mmol) and 4,5-dichlorophthalic anhydride (2.56 g, 11.93 mmol, 1.1eq) in methylene chloride (100 ml, DCM) was stirred for 2 h, whitesolids precipitated and the TLC showed disappearance of the startingmaterial. The solvent was removed, and the crude solid was loaded onto aflash chromatography column (28 g, SiO₂, sorbsil C-30, eluted with 1%MeOH in DCM; 0.5% of NH₄ OH was added towards the end of elution). Thematerial thus purified weighed 2.26 g as white crystals.Recrystallization twice from a large volume of hot ethanol (400 ml)yielded 1.57 g of white shining crystals, m.p.=132-134° C.

ANALYSIS: Calculated for C₂₂ H₁₈ Cl₂ FN₃ O₃ : 57.16% C 3.92% H 9.09% N;Found: 57.13% C 3.63% H 8.93% N

EXAMPLE 152N-[2-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]phthalimidehydrochloride

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (3.3 g, 14mmol), 2-bromoethylphthalimide (3.7 g, 14.7 mmol), K₂ CO₃ (2.0 g) andCH₃ CN (85 ml) was stirred and refluxed for 2.5 hours. The reaction waspoured into H₂ O and a white precipitate resulted, which was collectedto afford 2.0 g of product. The aqueous filtrate was extracted withCHCl₃, the extract washed (H₂ O), dried (MgSO₄) and was concentrated toafford 3.5 g of an off-white solid. Upon trituration of this solid withacetone, an additional 2.0 g of product was realized. The two sampleswere combined and suspended in MeOH (50 ml), and ethereal HCl was addeduntil the reaction mixture was acidic. After stirring for 1 hour atambient temperature, Et₂ O (50 ml) was added to afford 3.7 g of thehydrochloride salt. The salt was recrystallized from MeOH-Et₂ O to yield2.3 g (37%) of the compound as a white solid, m.p=271-273° C.

ANALYSIS: Calculated for C₂₂ H₂₀ FN₃ O₂ S.HCl: 59.25% C 4.75% H 9.42% N;Found: 58.99% C 4.60% H 9.33% N

EXAMPLE 153N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3,6-dichlorophthalimide

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.44g, 9.24 mmol) and 3,6-dichlorophthalic anhydride (2.01 g; 9.27 mmol) indichloromethane (DCM, 50 ml) was stirred at room temperature for 1 hour.White precipitates formed and the TLC of the reaction mixture showedthat there was no starting amine remaining. The solvent was strippeddown and the white solids which were poorly soluble in DCM were loadedonto a flash chromatography column, (SiO₂, 30 g) and the column waseluted with a solution of 1% CH₃ OH in DCM. The desired product thusobtained weighed 2.29 g (54%). Recrystallization from hot ethanolyielded 2.15 g of white crystals, m.p.=163-164° C.

ANALYSIS: Calculated for C₂₂ H₁₈ Cl₂ FN₃ O₃ : 57.16% C 3.92% H 9.09% N;Found: 57.16% C 3.64% H 9.13% N

EXAMPLE 154N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-chlorophthalimide

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.13g, 8.07 mmol), 4-chlorophthalic acid monosodium salt (2.2 g, 10 mmol)and dicyclohexylcarbodiimide (DCC, 4.25 g, 20.6 mmol) in acetonitrile(150 ml) was stirred at room temperature for 24 hours. The cloudymixture was filtered, then the solvent was stripped down. The residuewas partitioned between water and dichloromethane (DCM). The DCMsolution was washed with brine and dried over MgSO₄. The solvent wasremoved. The crude product was purified on a flash chromatography column(SiO₂, 35 g; eluted with DCM, and 1% CH₃ OH in DCM). The desired productthus obtained weighed 1.3 g. Recrystallization from ethanol yielded 590mg as white crystals, m.p.=170-171° C.

ANALYSIS: Calculated for C₂₂ H₁₉ FN₃ O₃ : 61.76% C 4.48% H 9.82% N;Found: 61.87% C 4.39% H 9.89% N

EXAMPLE 155N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-fluorophthalimide

A mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.37 g,8.98 mmol), 3-fluorophthalic acid (1.82 g, 9.9 mmol) anddicyclohexylcarbodiimide (DCC, 5.5 g, 26.7 mmol, 2.6 eq) indichloromethane (DCM, 250 ml) was stirred at room temperature for 18hours. The solids were filtered off. The organic solution wasconcentrated down. The residue was purified on a flash chromatographycolumn (SiO₂, 50 g; eluted with 1.4 liter; 2-6% CH₃ OH:DCM, 1 liter).The desired product thus obtained weighed 2.64 g (71%) as an off-whitesolid. Recrystallization from hot ethanol gave 1.41 g of white crystals,m.p.=142-143° C.

ANALYSIS: Calculated for C₂₂ H₁₉ F₂ N₃ O₃ : 64.22% C 4.66% H 10.21% N;Found: 64.11% C 4.70% H 10.14% N

EXAMPLE 156N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-fluorophthalimide

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (3.2 g,12 mmol), 4-fluorophthalic anhydride (freshly prepared according to theprocedure of Markezich, U.S. Pat. No. 3,956,321, 1976; 2.0 g, 12 mmol)and dicyclohexylcarbodiimide (DCC, 2.48 g, 12 mmol) in chloroform (100ml) was stirred at room temperature for 18 hours. The insolubles werefiltered off. The solution was loaded onto a flash chromatography column(SiO₂, 45 g) then was eluted with a solution of 2% methanol in methylenechloride. The fractions containing the desired product were pooled andconcentrated to yield 2.9 g of white solid. The material was convertedto a hydrochloride salt by treatment with a solution of hydrochloride inethanol. Recrystallization from ethanol gave the pure sample, 1.01 g,m.p.253-255° C.

ANALYSIS: Calculated for C₂₂ H₁₉ FN₃ O₃.HCl: 59.00% C 4.50% H 9.38% N;Found: 58.81% C 4.38% H 9.48% N

EXAMPLE 157N-[2-[4-(6-Flouro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-methylphthalimide

A mixture of2-[4-([6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.44g, 9.24 mmol), 4-methylphthalic anhydride (1.76 g, 10.8 mmol) anddicyclohexylcarbodiimide (2.1 g, 1.0 mmol) in dichloromethane (DCM, 100ml) was stirred at room temperature for 2 hours. The insolubles werefiltered off. The DCM solution was concentrated to a crude solid. Thiswas purified on a flash chromatography column (35 g, SiO₂, Sorbsil-C-30;eluted with 1% CH₃ OH in 99% DCM). The material thus purified weighed1.0 g (26%) as a white solid. Recrystallization from hot ethanol gave665 mg of crystals, m.p.=138-140° C.

ANALYSIS: Calculated for C₂₃ H₂₂ FN₃ O₃ : 67.80% C 5.44% H 10.31% N;Found: 67.67% C 5.48% H 10.30% N

EXAMPLE 158N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-4-methoxyphthalimide

A stirred mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.63g, 10 mmol) and 4-methoxyphthalic anhydride (1.78 g, 10 mmol) indichloromethane (100 ml) is stirred at room temperature for 3 hours. Thesolvent is then removed under reduced pressure and the residual materialis purified by flash chromatography. The product is purified further byrecrystallization to giveN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-methoxy-phthalimide.

EXAMPLE 159N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-nitrophthalimidehydrochloride

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.9 g,11 mmol), 4-nitrophthalic anhydride (2.33 g, 12.1 mmol) anddicyclohexylcarbodiimide (2.25 g, 11 mmol) in dichloromethane (DCM, 150ml) was stirred at room temperature for 16 hours. The mixture wasfiltered. The brownish solution was loaded onto a flash chromatographycolumn, (SiO₂, 35 g; eluted with DCM, then 2% CH₃ OH in DCM). Thedesired product thus obtained weighed 2.35 g (49%) as a pale whitesolid, m.p. 191-193° C. This solid was converted to the hydrochloridesalt by treatment with an HCl solution in ethanol to yield 1.54 g,m.p.=250-253° C. dec.

ANALYSIS: Calculated for C₂₂ H₁₉ FN₄ O₅.HCl 55.64% C 4.25% H 11.90% N;Found: 55.81% C 4.08% H 11.67% N

EXAMPLE 1604-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-2-hydroxybutanefumarate.

To a solution of ethyl3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate (3.21 g,10 mmol) in tetrahydrofuran (THF, 100 ml), was added methylmagnesiumbromide (10 ml, 30 mmol, 3M solution in ether) dropwise over 15 minutesat room temperature under N₂. The resulting mixture was stirred for 16hours. The mixture was slowly hydrolyzed with aqueous NH₄ Cl solution.The THF solution was diluted with EtOAc (300 ml), then was washed withwater and brine. The organic solution was separated and dried overMgSO₄. After removal of solvent, the crude product was purified by flashchromatography (25 g, SiO₂, eluted with 1 CH₃ OH:99 DCM). The materialthus purified weighed 2.36 g (77%) as white crystals. This was convertedto the fumarate salt by treatment with fumaric acid (895 mg) in ethanol.Recrystallization from ethanol yielded white crystals, 2.47 g,m.p.=156-158° C.

ANALYSIS: Calculated for C₁₇ H₂₃ FN₂ O₂.C₄ H₄ O₄ : 59.70% C 6.44% H6.63% N; Found: 59.40% C 6.27% H 6.28% N

EXAMPLE 161 Ethyl3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate fumarate

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7mmol), K₂ CO₃ (3.8 g, 27.5 mmol) and ethyl bromopropionate (5 g, 27.6mmol, 1.2 eq) in acetonitrile (200 ml) was heated at reflux for 16hours. The mixture was cooled and filtered. The solvent was removed, andthe residue was purified on a flash chromatography column (60 g, SiO₂,eluted with DCM). The material thus purified weighed 7.27 g (83%). Thefumarate salt was prepared by treatment of the free base (2.17 g) withfumaric acid (820 mg, 1.0 eq) in ethanol. Recrystallization from ethanolyielded 2.49 g of white crystals, m.p.=135-136° C.

ANALYSIS: Calculated for C₁₇ H₂₁ FN₂ O₃.C₄ H₄ O₄ : 57.79% C 5.77% H6.42% N; Found: 57.86% C 5.67% H 6.30% N

EXAMPLE 1622,3-dihydro-2-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-hydroxy-1H-isoindol-1-one

To a suspension ofN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimide(7.8 g, 19.8 mmol) in methanol (250 ml) and DCM (30 ml) was added NaBH₄(1.7 g, 45.5 mmol) at room temperature under nitrogen. After stirringfor 0.5 hours the homogeneous reaction mixture was concentrated. Theremaining solid was purified on a flash chromatography column (SiO₂, 1:1EtOAc/DCM, increased to 10% MeOH) to give 7.0 g (90%) of the desiredproduct as a solid which was recrystallized from EtOAc, m.p.=172-173° C.

ANALYSIS: Calculated for C₂₂ H₂₂ FN₃ O₃ : 66.82% C 5.61% H 10.63% N;Found: 66.63% C 5.52% H 10.51% N

EXAMPLE 1632,3-dihydro-2-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1H-isoindol-1-one

To2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3-hydroxy-1H-isoindol-1-one(2.2 g, 5.6 mmol) was added a solution of trifluoroacetic acid (11.0 ml)in dichloromethane (30 ml) at room temperature, under nitrogen.Triethylsilane (1.5 ml) was then added and the reaction mixture wasallowed to stir for 18 hours at which time it was poured into a NaHCO₃(sat.). The layers were separated and the aqueous phase was extractedwith DCM (3×). The combined organics were washed with brine and dried(Na₂ SO₄). Filtration and concentration gave the crude product as asolid which was recrystallized from EtOAc, to give 1.6 g (79%) of thedesired product as a white solid, m.p.=166-168° C.

ANALYSIS: Calculated for C₂₂ H₂₂ FN₃ O₂ : 69.64% C 5.84% H 11.07% N;Found: 69.37% C 5.70% H 11.00% N

EXAMPLE 164(S)-3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylpropylmethylcarbamate

To a solution of2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3hydroxy-1H-isoindol-1-one(3.1 g, 10.6 mmol) in dry THF (120 ml) was added methyl isocyanate (0.66ml, 11.1 mmol) followed by milled K₂ CO₃ (2.2 g, 15.9 mmol) at roomtemperature, under nitrogen. The reaction mixture was stirred for 3 daysat which time it was filtered through a pad of Celite and the solidswashed with EtOAc. The combined filtrates were concentrated to give thecrude product which was purified via flash column chromatography (silicagel, 2% Et₃ N/EtOAc). The product containing fractions were concentratedto give 2.7 g (73%) of the desired product as an oil which solidified onstanding. Recrystallization from EtOAc/pet.ether gave the product as asolid, m.p.=72-74° C.

ANALYSIS: Calculated for C₁₈ H₂₄ FN₃ O₃ : 61.88% C 6.92% H 12.03% N;Found: 61.82% C 7.02% H 11.77% N

EXAMPLE 165(S)-3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylpropyldecanoate fumarate

To a solution of2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3hydroxy-1H-isoindol-1-one(3.2 g, 10.9 mmol) in DCM (110 ml) was added decanoyl chloride (2.3 ml,10.9 mmol) at 0° C., under nitrogen. The reaction mixture was stirredfor 1.25 hours (0° C.) at which time it was poured into NaHCO₃ (sat.).The layers were separated and the aqueous phase was extracted with DCM(2×). The combined organics were dried, filtered and concentrated togive the crude product which was purified via flash columnchromatography (silica gel, 30% EtOAc/DCM). The product containingfractions were concentrated to give 3.4 g (70%) of the desired productas a yellow oil. The fumarate salt was prepared in ethanol with fumaricacid (1.05 eq.). The white salt was filtered and washed with isopropylether, m.p. 110-112° C.

ANALYSIS: Calculated for C₂₆ H₃₉ FN₂ O₃.C₄ H₄ O₄ : 64.04% C 7.70% H4.98% N; Found: 64.07% C 7.75% H 4.90% N

EXAMPLE 166(S)-6-Fluoro-3-[1-(3-methoxyphenyl-2-methylpropyl)-4-piperidinyl]-1,2-benzisoxazole

To a solution of2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3-hydroxy-1H-isoindol-1-one(3.3 g, 11.3 mmol) in dry THF (120 ml) was added potassium tert-butoxide(1.9 g, 16.9 mmol) followed by dimethyl sulfate (1.2 ml, 11.9 mmol) atroom temperature, under nitrogen. The reaction mixture was stirred for21 hours at which time it was filtered through a pad of Celite and thesolids washed with EtOAc. The combined filtrates were concentrated togive the crude product. Purification via flash column chromatography(silica gel, 0-20% acetone/DCM) afforded 1.6 g (46%) of the desiredproduct as a solid, m.p.=40-42° C.

ANALYSIS: Calculated for C₁₇ H₂₃ FN₂ O₂ : 66.65% C 7.57% H 9.14% N;Found: 66.49% C 7.48% H 9.12% N

EXAMPLE 167(±)-6-Fluoro-3-[1-(3-hydroxybutyl)-4-piperidinyl]-1,2-benzisoxazole

Racemic 3-hydroxybutyl tosylate was prepared in a manner described byFerreira et al., Tetrahedron, 46, pp. 6311-6318, (1990). To a solutionof the racemic tosylate (9.2 g, 37.7 mmol) in acetonitrile (190 ml) wasadded 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (8.3 g, 37.7 mmol)followed by milled potassium carbonate (7.8 g, 56.6 mmol) at roomtemperature under nitrogen. The reaction mixture was warmed to refluxfor 4.5 hours and allowed to cool to room temperature. The solids wereremoved via filtration through a pad of Celite and were washed withEtOAc. The combined filtrates were concentrated to give the crudeproduct. Purification via preparative HPLC (silica gel, 10% MeOH/EtOAc)afforded 6.3 g (57%), m.p.=100-102° C.

ANALYSIS: Calculated for C₁₆ H₂₁ FN₂ O₂ : 65.73% C 7.24% H 9.58% N;Found: 65.59% C 7.30% H 9.52% N

EXAMPLE 168(S)-6-Fluoro-3-[1-(3-hydroxy-2-methylpropyl)-4-piperidinyl]-1,2-benzisothiazolefumarate

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.6 g, 20mmol), (R)-(-)-3-bromo-2-methyl-1-propanol (3.0 g, 20 mmol), K₂ CO₃ (2.7g, 20 mmol), tetrabutylammonium sulfate (0.058 g), CH₃ CN (95 ml) and H₂O (19 ml) was stirred and refluxed for 4.5 hours. After standing atambient temperature for 16 hours, the reaction was poured into H₂ O, andsubsequent extractive workup of the aqueous with EtOAc yielded 6.8 g ofa partially solidified oil. The product was purified by flashchromatography on silica gel, eluting the column with CH₂ Cl₂, then 2%MeOH-CH₂ Cl₂ and finally 5% MeOH-CH₂ Cl₂. Concentration of theappropriate fractions yielded 5.2 g of a waxy solid. The solid wasdissolved in acetone and fumaric acid (1.9 g, 1.0 eq) was added and thereaction briefly heated at reflux. The resultant fumarate saltprecipitated from solution yielding 4.8 g of white solid. The compoundwas recrystallized from acetonitrile to yield 3.1 g (36%) of the alcoholas a white solid, m.p.=151-153° C .

ANALYSIS: Calculated for C₁₆ H₂₁ FN₂ OS.C₄ H₄ O₄ : 56.59% C 5.94% H6.60% N; Found: 56.31% C 5.96% H 6.48% N

EXAMPLE 169N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3,6-difluorophthalimide

A mixture of2-[4[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (1.53 g,5.8 mmol), 3,6-difluorophthalic anhydride (1.0 g, 5.43 mmol) anddicyclohexylcarbodiimide (DCC, 1.84 g, 8.9 mmol) in methylene chloride(DCM, 100 ml) was stirred for 6 hours, and then left standing overnightat room temperature. The solids were filtered off. The solution wasloaded onto a silica gel column (35 g, Sorbsil C-30), then eluted with amixture of methanol and DCM (1%-2%). The fractions containing thedesired product were pooled and concentrated to give 1.23 g of whitesolid. Recrystallization from DCM and hot ethanol yielded 1.03 g (44.5%)of white crystals, m.p.=144-145° C.

ANALYSIS: Calculated for C₂₂ H₁₈ F₃ N₃ O₃ : 61.54% C 4.23% H 9.79% N;Found: 61.63% C 3.83% H 9.77% N

EXAMPLE 170N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,2,3,4-tetrahydro-isoquinoline-1,3-dione

A mixture of2-[4[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.45 g,9.28 mmol), homophthalic anhydride (1.78 g, 10.9 mmol) and DCC (2.2 g,10.7 mmol) in CHCl₃ (100 ml) was stirred at room temperature for 3.5hours. The insolubles were filtered off. The solution was loaded onto aflash chromatography column (Sorbsil C-30, 40 g), eluted with DCM (1.51), 2% CH₃ OH in DCM (1 l), then washed with 20% CH₃ OH in DCM. Thefractions containing the front spot were pooled and concentrated to give500 mg of yellow solid. This solid was recrystallized again from ethanolto provide 340 mg (10.7%) of crystals, m.p.=148-150° C.

ANALYSIS: Calculated for C₂₃ H₂₂ FN₃ O₃ : 67.80% C 5.44% H 10.31% N;Found: 67.54% C 5.31% H 10.17% N

EXAMPLE 1712-[4-[(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]aminesesquifumarate

To a stirred solution ofN-[2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]phthalimide(17.0 g, 42 mmol) and MeOH (200 ml) under N₂ was added, dropwise,hydrazine monohydrate (4.2 g, 83 mmol). After complete addition, thereaction was stirred at reflux for 17 hours. The reaction mixture wasconcentrated and the resultant residue was dissolved in H₂ O. Theaqueous solution was acidified to pH ˜2 with concentrated HCl and theprecipitate was filtered. The filtrate was basified with 50% NaOH andthe product was extracted into CH2Cl₂. The CH₂ Cl₂ extract was washedwith H₂ O, dried with MgSO₄ and concentrated to yield 6.0 g (52%) of abeige oil. A 5.8 g sample of the oil (21 mmol) was warmed in EtOH (100ml) and fumaric acid (2.7 g, 23 mmol) was added. The solution wasrefluxed gently for 15 minutes and was stirred at ambient temperaturefor 1.5 hours Anhydrous Et₂ O (400 ml) was added and the productcollected to yield 7.1 g of an off-white powder. A portion (3.0 g) wasrecrystallized from MeOH-Et₂ O to provide 1.7 g (22%) of thesesquifumarate salt as a white powder m.p.=169-171 ° C.

ANALYSIS: Calculated for C₁₄ H₁₈ FN₃ S.1.5C₄ H₄ O₄ : 52.97% C 5.35% H9.27% N; Found: 52.96% C 5.44% H 9.39% N

EXAMPLE 172(S)-6-Fluoro3-[1-(3-hydroxybutyl)-4-piperidinyl]-1,2-benzisoxazole

(S)-Hydroxybutyl tosylate was prepared in a manner described by Ferreiraet al., Tetrahedron, 46, pp. 6311-6318, (1990). To a solution of thetosylate (6.8 g, 28.0 mmol) in acetonitrile (150 ml) was added6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (6.2 g, 28.0 mmol) followedby milled potassium carbonate (5.8 g, 42.0 mmol) at room temperatureunder nitrogen. The reaction mixture was warmed to reflux for 3 hoursand allowed to cool to room temperature. The solids were removed viafiltration through a pad of Celite and were washed with EtOAc. Thecombined filtrates were concentrated to give the crude product.Purification via flash column chromatography (silica gel, 0-10%MeOH/EtOAc) afforded 5.5 g (67%) of the desired product as an oil whichsolidified on standing, m.p.=84-86° C.

ANALYSIS: Calculated for C₁₆ H₂₁ FN₂ O₂ : 65.73% C 7.24% H 9.58% N;Found: 65.58% C 6.83% H 9.50% N

EXAMPLE 173(R)-6-Fluoro-3-[1-(3hydroxybutyl)-4-piperidinyl]-1,2-benzisoxazole

(R)-Hydroxybutyl tosylate was prepared in a manner described by Ferreiraet al., Tetrahedron, 46, pp. 6311-6318, (1990). To a solution of thetosylate (8.4 g, 34.2 mmol) in acetonitrile (120 ml) was added6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (7.5 g, 34.2 mmol) followedby milled potassium carbonate (7.1 g, 51.3 mmol) at room temperatureunder nitrogen. The reaction mixture was warmed to reflux for 2 hoursand allowed to cool to room temperature. The solids were removed viafiltration through a pad of Celite and were washed with EtOAc. Thecombined filtrates were concentrated to give the crude product.Purification via flash column chromatography (silica gel, 10%MeOH/EtOAc) afforded 6.0 g (60%) of the desired product as an oil whichsolidified on standing, m.p.=82-84° C.

ANALYSIS: Calculated for C₁₆ H₂₁ FN₂ O₂ : 65.73% C 7.24% H 9.58% N;Found: 65.66% C 7.13% H 9.53% N

EXAMPLE 174N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide

A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (4.0 g, 18 mmol), K₂CO₃ (2.7 g, 20 mmole), N-(2-bromoethyl)phthalimide (4.8 g, 19 mmole) andCH₃ CN (100 ml) was stirred at reflux under N₂ for 4 hours. Afterstanding at ambient temperature for 65 hours, the reaction was pouredinto H₂ O. The resultant solid was collected to yield 4.0 g of a yellowpowder. The product was recrystallized twice from ethanol to yield 3.5 g(50%) of a beige powder m.p.=220-223° C.

ANALYSIS: Calculated for C₂₁ H₂₀ FN₅ O₂ : 64.11% C 5.12% H 17.80% N;Found: 64.16% C 5.04% H 17.82% N

(A) N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimidehydrochloride

A 5.0 g sample ofN-[2-[4(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-ethyl]phthalimide wassuspended in methanol (130 ml) and was made acidic with ethereal.HCl.After stirring for 1 hour, anhydrous ether (100 ml) was added and thesuspension was stirred for an additional 30 minutes. The solid wascollected and dried to afford 4.5 g of an off-white powder. This wascombined with an additional sample (7.3 g total) and recrystallizationfrom MeOH gave 4.3 g of the salt as an off-white powder, mp=265-268° C.

ANALYSIS: Calculated for C₂₁ H₂₀ FN₅ O₂.HCl: 58.62% C 4.92% H 16.29% N;Found: 58.60% C 4.83% H 16.19% N

EXAMPLE 175 Ethyl3-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propionatehydrochloride

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (6.0 g, 25mmol), ethyl 3-bromopropionate (4.5 g, 25 mmol), K₂ CO₃ (3.5 g) and CH₃CN (100 ml) was stirred and refluxed for 16 hours. The reaction waspoured into H₂ O, and after extractive workup with EtOAc, 6.0 g of anorange oil was realized. The oil was dissolved in Et₂ O and ethereal HClwas added to precipitate 6.3 g of a white hydrochloride salt. The saltwas recrystallized from CH₃ CN to yield 6.0 g (64%) of the desiredcompound. An analytical sample was obtained by recrystallization of a1.0 g sample from EtOH-Et₂ O to yield 0.8 g of a white solid,m.p.=197-199° C.

ANALYSIS: Calculated for C₁₇ H₂₁ FN₂ O₂ S.HCl: 54.76% C 5.95% H 7.51% N;Found: 54.77% C 5.99% H 7.28% N

EXAMPLE 1764-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]-2-methyl-2-hydroxybutanehemifumarate

To a stirred solution, under N₂, of ethyl3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propionate (3.1 g,9 mmol), in THF (100 ml) was added, dropwise, methylmagnesium bromide(9.0 ml, 27 mmol of a 3M solution in ether). The reaction was stirred atambient temperature for 16 hours and then a saturated solution NH₄ Clwas added dropwise, with cooling. The reaction was further diluted withH₂ O, and after extractive workup of the aqueous mixture with EtOAc, 2.8g of a waxy solid resulted. The solid was dissolved in EtOAc and 3.0 gof fumaric acid was added, and 5.0 g of a fumarate salt was collected,which was contaminated with unreacted fumaric acid. The crude salt wasrecrystallized from MeOH-Et₂ O, and then from DMF to afford 1.6 g(45.7%) of the desired compound as a hemifumarate, m.p.=237-239° C.

ANALYSIS: Calculated for C₁₇ H₂₃ FN₂ OS.C₄ H₄ O₄ : 59.98C% 6.64% H 7.36%N; Found: 59.75% C 6.65% H 7.39% N

EXAMPLE 177N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-hydroxyphthalimidehydrochloride

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.48g, 9.3 mmol), 3-hydroxyphthalic anhydride (1.8 g, 10.9 mmol) anddicyclohexylcarbodiimide (2.2 g, 10.7 mmol) in chloroform (100 ml) wasstirred at room temperature for 48 hours. The mixture was filtered. Theyellow solution was loaded onto a flash chromatography column (SiO₂, 40g; eluted with DCM, 1 l; and 2% CH₃ OH in DCM, 1 l). The desired productthus obtained as a light yellow solid weighed 2.12 g (55%),m.p.=156-157° C. This material was converted to the hydrochloride saltby treatment with a solution of hydrochloric acid in ethanol. Theoff-white crystals were collected: 1.97 g, m.p.=270-272° C. dec.

ANALYSIS: Calculated for C₂₂ H₂₀ FN₃ O₄.HCl: 59.26% C 4.75% H 9.42% N;Found: 59.34% C 4.70% H 9.19% N

EXAMPLE 178N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-fluorophthalimide

A solution of2-[4-[(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]amine (2.7g, 10 mmol), 4fluorophthalic anhydride (1.6 g, 10 mmol) and DMF (50 ml)was stirred under N₂ at ambient temperature for 1 hour and then at 70°for 2 hours. Most of the DMF was removed in vacuo to afford 4.6 g of adamp, beige solid. The compound was dissolved in anhydrous Et₂ O (100ml) and MeOH (75 ml) and the insolubles were filtered off. The filtratewas made acidic with ethereal HCl to precipitate the HCl salt.Additional anhydrous Et₂ O (500 ml) was added and the salt was collectedto give 3.5 g of a beige solid. Recrystallization from EtOH provided 2.0g (44%) of an off-white powder, m.p.=269-271° C.

ANALYSIS: Calculated for C₂₂ H₁₉ F₂ N₃ O₂ S.HCl: 56.96% C 4.35% H 9.06%N; Found: 57.33% C 4.33% H 9.11% N

EXAMPLE 1796-Fluoro-3-[1-(3-hydroxy-3ethylpentyl)-4-piperidinyl]-1,2-benzisoxazole

To a solution of ethyl3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate (3.9 g,12.0 mmol) in THF (100 ml) was added ethylmagnesium bromide (12.0 ml,36.0 mmol, 3.0M in ether) at room temperature under nitrogen (mildexotherm). The reaction mixture was stirred for 17 hours at which timeit was carefully quenched with NH₄ Cl (sat., 20 ml). The precipitatedsalts were dissolved into water (25 ml) and the layers were separated.The aqueous phase was extracted with EtOAc (2×) and the combinedorganics were washed with brine and dried (Na₂ SO₄). Filtration andconcentration gave the crude product which was purified via flash columnchromatography (silica gel, 1% MeOH/DCM) to give 2.4 g (61%) of thedesired product as an oil which solidified on standing, m.p.=50-53° C.

ANALYSIS: Calculated for C₁₉ H₂₇ FN₂ O₂ : 68.24% C 8.14% H 8.38% N;Found: 67.99% C 8.11% H 8.48% N

EXAMPLE 180 Decanoic acid2-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-ylester

To a solution of2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-2,3-dihydro-3-hydroxy-1H-isoindol-1-one(1.4 g, 3.5 mmol) in DCM (30 ml) was added Et₃ N (1.2 ml, 8.8 mmol)followed by decanoyl chloride at 0° C. under nitrogen. After stirringfor 1 h in the cooling bath, the solvent was removed using a stream ofnitrogen. The remaining residue was diluted with EtOAc and theprecipitated triethylamine hydrochloride was filtered off. The filtratewas concentrated and the remaining oil was flushed through alumina withether to give 1.6 g (83%) of the desired product as a yellow oil.

ANALYSIS: Calculated for C₃₂ H40FN₃ O₄ : 69.92% C 7.33% H 7.64% N;Found: 69.70% C 7.39% H 7.56% N

EXAMPLE 1816-Chloro-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1H-benz[de]isoquinoline-1,3(2H)-dione

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.32g, 8.8 mmol) and 4-chloro-1,8-naphthalic anhydride (2.45 g, 10.5 mmol,1.25 eq) in chloroform (120 ml) was stirred at room temperatureovernight. To the mixture was added 5 ml of methanol and the solutionwas concentrated down to 20 ml. The resulting mixture was loaded onto aflash chromatography column (SiO₂, 50 g; eluted with dichloromethane,DCM, 1l, and 2% CH₃ OH in DCM, 1 l). The product thus obtained as alight yellow solid weighed 2.61 g. Recrystallization from CH₂ Cl₂/ethanol gave 2.5 g of pale white crystals, m.p.=207-209° C.

ANALYSIS: Calculated for C₂₆ H₂₁ CIFN₃ O₃ : 65.34% C 4.43% H 8.79% N;Found: 64.87% C 4.32% H 8.67% N

EXAMPLE 182N-[2-[4-(6Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-tert-butylphthalimidefumarate

A mixture of2-[4[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.0 g,7.57 mmol) and 4-(t-butyl)phthalic anhydride (1.62 g, 7.94 mmol) indimethylformamide (DMF, 20 ml) was heated at 135° C. for 3 hours. Thesolvent was removed on a rotary evaporator under vacuum, and furtherdried on a vacuum pump. The residue was purified by flash chromatographyover a silica gel column (SiO₂, 35 g; eluted with DCM, and 1-2% ofmethanol in DCM). The product thus obtained as an oil was trituratedwith isopropyl ether and dried to a waxy solid. This solid was convertedto the fumarate salt by treatment with a solution of fumaric acid (778mg) in ethanol. The crystals were collected and weighed: 3.03 g;m.p.=198-199° C.

ANALYSIS: Calculated for C₂₆ H₂₈ FN₃ O₃.C₄ H₄ O₄ : 63.71% C 5.70% H7.43% N; Found: 63.46% C 6.05% H 7.27% N

EXAMPLE 183N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimidehydrochloride

A mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (2.5 g, 11 mmol),2-bromoethylphthalimide (3.0 g, 10 mmol), NaHCO3 (1.0 g) and DMF (30 ml)was stirred and heated at 60° C. for 2.5 hours. The reaction was pouredinto H₂ O, and after extractive workup with EtOAc there remained 4.0 gof a golden oil. The oil was dissolved in EtOAc and ethereal HCl wasadded to yield 1.9 g of the hydrochloride salt as a white solid. Thesolid was recrystallized from MeOH-Et₂ O and then from DMF to afford0.54 g (11%) of the compound as a white solid, m.p.=270-272° C.

ANALYSIS: Calculated for C₂₂ H₂₁ FN₄ O₂ HCl: 61.61% C 5.17% H 13.06% N;Found: 61.50% C 5.05% H 12.86% N

EXAMPLE 1842-[2-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]-2,3-dihydro-3-hydroxy-1H-isoindol-1-onehydrochloride

To a stirred solution of theN-[2-[4-(6fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]phthalimide(2.5 g, 6 mmol) in MeOH (50 ml)-CH₂ Cl₂ (20 ml) was added NaBH₄ (0.8 g,21 mmol). The reaction was stirred at ambient temperature for 2 hours,and then the solvent was evaporated. The residue was diluted with H₂ O,and extractive workup of the aqueous with CH₂ Cl₂ afforded 2.2 g of abeige solid. The solid was combined with a sample from a prior run , andthe combined sample (3.2 g) was chromatographed on a Waters Prep 500 LC,eluting with EtOAc-Et₂ NH (5%). Concentration of the appropriatefractions afforded 2.2 g of a white solid. The solid was dissolved inEtOAc and ethereal HCl was added to yield 2.0 g of a hydrochloride salt.The salt was recrystallized first from EtOH and then from DMF to yield1.2 g (31%) of a white solid, m.p.=210-212° C.

ANALYSIS: Calculated for C₂₂ H₂₂ FN₃ O₂ S.HCl: 58.99% C 5.18% H 9.38% N;Found: 58.89% C 5.23% H 9.16% N

EXAMPLE 185N-[2-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]-4-methylphthalimidehydrochloride

A mixture of2-[4[(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]amine (3.4g, 12 mmol), 4methylphthalic anhydride (2.0 g, 12 mmol) and DMF (75 ml)was stirred at 70° C. under N₂ for 3.5 hours. Most of the DMF wasremoved in vacuo, and the oily residue was diluted with H₂ O. EtOAc wasadded to the aqueous mixture and the biphase was filtered through Celiteto remove an insoluble yellow solid. The solid was scraped away from theCelite and was dissolved in CH₂ Cl₂. The solution was filtered throughthe original Celite cake, and the CH₂ Cl₂ filtrate was washed with H₂ O,dried with MgSO₄ and concentrated to yield 0.5 g (10%) of an off-whitesolid.

The phases of the EtOAc/H₂ O filtrate were separated and the aqueous wasfurther extracted with EtOAc. The EtOAc extract was washed with H₂ O,dried with MgSO₄ and concentrated to afford 3.5 g (69%) of an off-whitesolid.

The two samples were combined and recrystallized from EtOH to give 2.2 gof a white powder. The product was dissolved in anhydrous ether (200 ml)and methanol (100 ml) and the solution was made acidic with etherealHCl. After ca. 30 minutes of stirring the salt began to precipitate.Additional anhydrous ether (400 ml) was added over 2 hours and theresultant white solid was collected to yield 2.2 g. Recrystallizationfrom MeOH-ether provided 1.7 g (30%) of a white powder, m.p.=268-271° C.

ANALYSIS: Calculated for C₂₃ H₂₂ FN₃ O₂ S.HCl: 60.06% C 5.04% H 9.14% N;Found: 60.01% C 5.00% H 9.12% N

EXAMPLE 1866-Fluoro-3-[1-(3-hydroxy-3propylhexyl)-4-piperidinyl]-1,2-benzisoxazolehydrochloride

To a solution of ethyl3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propionate (4.5 g,14.0 mmol) in THF (120 ml) was added propylmagnesium chloride (21.1 ml,42.0 mmol, 2.0M in ether) at room temperature under nitrogen (mildexotherm). The reaction mixture was stirred for 17 hours at which timeit was carefully quenched with NH₄ Cl (sat., 30 ml). The layers wereseparated and the aqueous phase was extracted with EtOAc (2×). Thecombined organics were washed with brine and dried (Na₂ SO₄). Filtrationand concentration gave the crude product which was purified via flashcolumn chromatography (silica gel, 2% Et₃ N/ether). After flushing theproduct through alumina with ether, the hydrochloride salt was preparedin ether/EtOAc (1:1, 40 ml, 1 drop IPA) with ethereal HCl to give 2.5 g(45%) of the desired product as a white solid, m.p.=163-164° C.

ANALYSIS: Calculated for C₂₁ H₃₁ FN₂ O₂.HCl: 63.22% C 8.08% H 7.02% N;Found: 62.97% C 7.95% H 7.01% N

EXAMPLE 187

N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-nitrophthalimidefumarate

A mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (2.09g, 7.9 mmol) and 3-nitrophthalic anhydride (1.6 g, 8.3 mmol, 1.05 eq) indimethylformamide (DMF, 20 ml) was heated at 135° C. for 3 hours. Thesolvent was removed on a rotary evaporator under vacuum and furtherdried on a vacuum pump. The residue was purified by flash chromatographyover a silica gel column (SiO₂, 35 g; eluted with dichloromethane, 300ml, and 3% CH₃ OH in DCM, 300 ml). The product thus obtained, 2.01 g,was dissolved into DCM (15 ml) and ethanol (5 ml) and was treated with asolution of fumaric acid (530 mg, 1.0 eq) in ethanol (15 ml). Thecrystals were collected and weighed: 2.03 g, m.p.=237-239° C.

ANALYSIS: Calculated for C₂₂ H₁₉ FN₄ O₅.C₄ H₄ O₄ : 56.32% C 4.18% H10.10% N; Found: 55.94% C 4.23% H 9.87% N

EXAMPLE 188N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-hydroxyphthalimidehydrochloride

A mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (5 g,18.9 mmol), 4hydroxyphthalic acid (4.14 g, 1.2 eq), anddicyclohexylcarbodiimide (DCC, 8.61 g, 4.18 mmol) in dimethylformamide(50 ml, DMF) was stirred and heated at 75° C. for 18 hours. The mixturewas cooled, and the solids (DCU) were filtered and rinsed withdichloromethane (DCM). The solution was concentrated down to dryness.The residue was dissolved into dichloromethane (100 ml) and theinsolubles, which contained the product also, were filtered andcollected. The solution was concentrated down to 50 ml and loaded onto aflash chromatography column (SiO₂, 50 g; eluted with DCM, andmethanol:DCM mixture). The desired product was collected as a pinkishsolid, 1.71 g. This solid was converted to the hydrochloride salt inethanol with an HCl in ether solution (1M, 5 ml). The crystals werecollected and dried; weight: 1.2 g; m.p.=272-275° C. dec.

ANALYSIS: Calculated for C₂₂ H₂₀ FN₃ O₄.HCl: 59.26% C 4.75% H 9.42% N;Found: 59.08% C 4.60% H 9.34% N

EXAMPLE 189(±)-6-Fluoro-3-[1-(3-hydroxybutyl)-4-piperidinyl]-1,2-benzisothiazolehydrochloride

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (3.9 g, 17mmol), K₂ CO₃ (2.3 g, 17 mmol, (±)-3-hydroxybutyl tosylate (4.0 g, 16mmol) and CH₃ CN (100 ml) was stirred at reflux under N₂ for 5 hours.The cooled reaction was filtered through Celite and the cake was rinsedwith EtOAc. The filtrate was concentrated to afford 6.7 g of a red oil.Purification via preparative HPLC (Water's Associates Prep LC/System500, using 2 silica gel columns and 10% MeOH-CH₂ Cl₂) provided 2.5 g ofa beige solid. The product was dissolved in anhydrous Et₂ O and aminimal amount of MeOH and the solution was acidified with ethereal HCl.Additional Et₂ O was added to precipitate 1.9 g of the HCl salt.Recrystallization from MeOH-Et₂ O gave 1.7 g and a secondrecrystallization from CH₃ CN yielded 1.0 g (18%) of a light beigepowder, m.p.=182-184° C.

ANALYSIS: Calculated for C₁₆ H₂₁ FN₂ OS.HCl: 55.72% C 6.43% H 8.12% N;Found: 55.83% C 6.54% H 8.19% N

EXAMPLE 190 Decanoic acid1,1-diethyl-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propylester hydrochloride

To a solution of6-fluoro-3-[1-(3-hydroxy-3-ethylpentyl)-4-piperidinyl]-1,2-benzisoxazole(2.5 g, 7.48 mmol) in DCM (100 ml) was added decanoyl chloride (1.5 ml,7.48 mmol) at 0° C., under nitrogen. The reaction mixture was stirredfor 4 days at which time it was poured into NaHCO₃ (sat., 50 ml). Thelayers were separated and the aqueous phase was extracted with DCM (2×).The combined organics were dried, filtered and concentrated to give thecrude product which was purified via flash column chromatography (silicagel, 20-40% EtOAc/DCM). The product containing fractions wereconcentrated to give 3.0 g (81%) of the desired product as a yellow oil.The hydrochloride salt was prepared in anhydrous ether (60 ml) andisopropanol (1 ml) with ethereal HCl. The white salt was filtered andwashed with anhydrous ether, m.p.=159-161° C.

ANALYSIS: Calculated for C₂₉ H₄₅ FN₂ O₃.HCl: 66.33% C 8.83% H 5.33% N;Found: 66.45% C 9.01% H 5.31% N

EXAMPLE 191N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-naphthalimide

A mixture of2-[4(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.0 g,7.58 mmol), and 2,3-naphthalenedicarboxylic anhydride (1.58 g, 7.95mmol) in dimethylformamide (20 ml, DMF) was heated at 150° C. for 2hours. At the end, the mixture was cooled and the solvent was removed todryness. The residue was purified by flash chromatography over silicagel column (60 g of SiO2, eluted with dichloromethane (DCM), and 1.5%CH₃ OH in DCM). The product crystallized out on concentration; weight:1.6 g (47%). Recrystallization from chloroform:ethanol gave 1.38 g ofoff-white crystals, m.p.=192-193° C.

ANALYSIS: Calculated for C₂₆ H₂₂ FN₃ O₃ : 70.42% C 5.00% H 9.48% N;Found: 69.85% C 4.59% H 9.27% N

EXAMPLE 1922,3-Dihydro-2-[2-[4-(6fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-hydroxy-3-methyl-1H-isoindol-1-onefumarate

To the solution ofN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]phthalimide(6.2 g, 15.87 mmol) in tetrahydrofuran (THF, 80 ml) was added dropwise asolution of methylmagnesium bromide (3M, 6.5 ml, 1.2 eq) in ether atroom temperature under N₂. The mixture was stirred at 55° C. for 16hours. The reaction mixture was treated with NH₄ Cl solution (10 ml) andpartitioned between brine and ethyl acetate. The EtOAc solution waswashed with brine and dried. Filtration and concentration gave a crudeproduct (3.9 g). This crude product was purified on a flashchromatography column (40 g, SiO₂, eluted with 0.5% CH₃ OH in DCM). Thepure product (1.75 g, 27%) thus obtained was treated with fumaric acid(500 m, 1.0 eq) in ethanol to yield 1.8 g, m.p.=167-168° C.

ANALYSIS: Calculated for C₂₃ H₂₄ FN₃ O₃.C₄ H₄ O₄ : 61.71% C 5.37% H8.00% N; Found: 61.47% C 5.67% H 7.82% N

EXAMPLE 1932,3-Dihydro-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-methylene-1H-isoindol-1-onehydrochloride

To the solution of2,3-dihydro-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-hydroxy-3-methyl-1H-isoindol-1-one(4.88 g, 11.9 mmol) in chloroform (50 ml) was added HCl ether (1M, 20ml) solution. A precipitate formed. This mixture was stirred for 18hours at room temperature. The mixture was basified with triethylamineand washed with brine. The organic solution was dried and concentratedto a crude material. The purification was done by flash chromatographyover silica gel column (SiO₂, 60 g; eluted with DCM). The pure productthus obtained weighed 3.28 g (70%). Treatment with HCl ether solution inethanol gave 1.52 g of white crystals, m.p.=261-263° C.

ANALYSIS: Calculated for C₂₃ H₂₀ FN₃ O.HCl: 64.56% C 5.42% H 9.82% N;Found: 64.47% C 5.51% H 9.72% N

EXAMPLE 1941-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]cyclohexanolhydrochloride

To pentamethylene bis(magnesium bromide) (35.0 ml, 17.5 mmol, 0.5M inTHF) was added a solution of ethyl3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propionate (5.6 g,17.5 mmol) in THF (100 ml) at 0° C., under nitrogen-mild exotherm. Thereaction mixture was warmed to room temperature and stirred for 17 hoursat which time it was carefully quenched with NH₄ Cl (sat., 50 ml). Theprecipitated salts were dissolved into water (25 ml) and the layers wereseparated. The aqueous phase was extracted with EtOAc (2×) and thecombined organics were then dried (Na₂ S₄). Filtration and concentrationgave the crude product which was purified via flash columnchromatography (silica gel, 50% EtOAc/DCM then 100% EtOAc) to give 2.8 g(46%) of the desired product as a white solid. The hydrochloride saltwas prepared in anhydrous ether (125 ml) and methanol (15 ml) withethereal HCl, m.p.=210° C. (dec.).

ANALYSIS: Calculated for C₂₀ H₂₇ FN₂ O₂.HCl: 62.74% C 7.37% H 7.32% N;Found: 62.85% C 7.53% H 7.14% N

EXAMPLE 1955-[4-(6-Fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]-3-ethyl-3-hydroxypentanehydrochloride

To a stirred solution, under N₂, of ethyl3-[4-(6-fluoro-1,2-benzisothiazol-3yl)-1-piperidinyl]propionate (5.3 g,16 mmol) in THF (200 ml), was added dropwise, ethyl magnesium bromide(15.7 ml of a 3.0M solution in Et₂ O). The reaction was stirred atambient temperature for 16 hours and then following cooling in an icebath, a saturated solution of NH₄ Cl was added dropwise. The aqueousmixture was extracted with EtOAc, and the extract was washed (H₂ O),dried (MgSO₄) and the solvent was concentrated to afford 5.8 g of ayellow oil. The oil was chromatographed on a preparative HPLC, upon asilica gel column, eluting with 6% MeOH/CH₂ Cl₂. Concentration of theappropriate fractions yielded 3.7 g of a yellow oil. The oil wasdissolved in Et₂ O and ethereal HCl was added to precipitate 4.0 g of awhite salt. The salt was recrystallized twice from EtOH-Et₂ O to afford1.4 g (22%) of the alcohol as a white solid, m.p.=207-209° C.

ANALYSIS: Calculated for C₁₉ H₂₇ FN₂ OS.HCl: 58.98% C 7.29% H 7.24% N;Found: 58.95% C 7.63% H 7.11% N

EXAMPLE 196 Ethyl3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propionate hydrochloride

To a stirred suspension of 6-fluoro-3-(4-piperazinyl)-1H-indazole (9.9g, 45 mmol), K₂ CO₃ (6.8 g, 49 mmol) and CH₃ CN (210 ml) under N₂ wasadded, dropwise, ethyl 3-bromopropionate (8.1 g, 45 mmol) in CH₃ CN (20ml). After complete addition, the reaction was stirred at reflux for16.5 hours. A TLC revealed remaining starting indazole; therefore,triethylamine (1.5 g, 14 mmol) was added dropwise to the cool reactionmixture. The reaction was stirred at reflux for 1 hour longer with noadditional change by TLC. The reaction was cooled, filtered, and thefiltrate concentrated to yield 14.6 g of an off-white solid. Thematerial was purified by preparative HPLC (Water's Associates PrepLC/System 500A using 2 silica gel columns and 6.5% MeOH-CH₂ Cl₂ aseluent). Concentration of appropriate fractions gave 8.1 g (51%) of agrey-white solid. A 1.5 g sample was dissolved in MeOH (45 ml) and wasacidified with ethereal HCl. The solution was stirred for 5 minutes andanhydrous ether (50 ml) was added. Within one minute the HCl saltprecipitated. More anhydrous ether (100 ml) was added and the salt wascollected and dried to yield 1.5 g of a white solid. Recrystallizationfrom ethanol provided 1.2 g (37%) of fluffy white crystals,m.p.=224-226° C.

ANALYSIS: Calculated for C₁₆ H₂₁ FN₄ O₂.HCl: 53.86% C 6.21% H 15.70% N;Found: 53.81% C 5.88% H 15.37% N

EXAMPLE 1974-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methylbutyldecanoate fumarate

To a mixture of4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-2-butanol(4.68 g, 15.3 mmol) and triethylamine (2.23 g, 22.3 mmol) in chloroform(20 ml) was added decanoyl chloride (3.5 g, 18.4 mmol, 1.2 eq) dropwiseat 0° C. The reaction was stirred at ambient temperature for 4 hours.The solvent was removed. The residue was purified by flashchromatography over a silica gel column (SiO₂, 65 g, eluted with DCM, 1l, 1% CH₃ OH in DCM, 1 l). The product thus purified weighed 5.7 g (80%)as an oil. This oily product was converted to the fumarate salt inethanol with fumaric acid (1.51 g, 1.0 eq) to yield 3.34 g,m.p.=133-134° C.

ANALYSIS: Calculated for C₂₇ H₄₁ FN₂ O₃.C₄ H₄ O₄ : 64.56% C 7.87% H4.86% N; Found: 64.42% C 7.74% H 4.78% N

EXAMPLE 1982-[2-[4-(6-Fluoro1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3-methyl-1H-isoindol-1-onehydrochloride

A mixture of2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3-hydroxy-3-methyl-1H-isoindol-1-one(3.96 g, 9.7 mmol) and lithium aluminum hydride (1.1 g, 50% in oil, 1.5eq) in tetrahydrofuran (50 ml) was stirred at room temperature for 16hours. The mixture was quenched carefully with a small amount of ice,then was diluted with ethyl acetate (200 ml). The mixture was stirredfor 20 minutes. The insolubles were filtered. The organic solution wasdried over MgSO₄ and concentrated down to a yellow oil (4.5 g). This oilwas purified by flash chromatography over silica gel column (SiO₂, 58 g;eluted with DCM, 1 l , and 1% CH₃ OH in DCM). Only 1.91 g of desiredproduct was obtained. This material was treated with HCl (1M HCl inether, 6 ml) in ethanol followed by isopropyl ether to yield 1.48 g(36%), m.p.=213-215° C.

ANALYSIS: Calculated for C₂₃ H₂₄ FN₃ O₂.HCl: 64.25% C 5.86% H 9.77% N;Found: 63.88% C 5.74% H 9.44% N

EXAMPLE 1991-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]cyclopentanolhydrochloride

In a flame-dried 500 ml round-bottom flask, equipped with additionfunnel and condenser, was placed magnesium metal (3.4 g, 140 mmol) andanhydrous ether (20 ml). A solution of 1,4-dibromobutane (4.4 ml, 36.5mmol) in anhydrous ether (10 ml) was then syringed into the additionfunnel and added dropwise to the magnesium metal. Initially no reactiontook place, but with the addition of a few crystals of iodine and gentleheating the Grignard reagent began to form. The rate of addition wassuch that a gentle reflux was maintained. Upon complete addition, theGrignard was stirred for 0.5 hours. A solution of3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propionate (9.0 g,28.1 mmol) in THF (75 ml) was then added (dropwise, exothermic) at roomtemperature and stirred for 21.5 hours. The reaction mixture wascarefully quenched with NH₄ Cl (sat., 100 ml) and the precipitatedmagnesium salts were dissolved into water (50 ml). The layers wereseparated and the aqueous phase was extracted with EtOAc (2×). Thecombined organics were dried (Na₂ SO₄), filtered and concentrated togive the crude product. Purification via flash column chromatography(silica gel, 50% EtOAc/DCM) gave 6.2 g (67%) of the desired product as awhite solid. The hydrochloride salt was prepared in EtOAc (50 ml), ether(40 ml), and methanol (5 ml) with ethereal HCl, m.p. 185-188° C.

ANALYSIS: Calculated for C₁₉ H₂₅ FN₂ O₂.HCl: 61.87% C 7.10% H 7.59% N;Found: 61.79% C 7.09% H 7.53% N

EXAMPLE 2004-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]-2-hydroxy-2-methylbutanehydrochloride

To a stirred solution of ethyl3-[4(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propionate (5.0 g, 16 mmol)in THF (120 ml) under N₂ was added, dropwise, methylmagnesium bromide(15.6 ml of a 3.0M solution in Et2O; 0.047 mol). The temperature wasmaintained below 30° C. during the addition by using a water bath. Aftercomplete addition, the reaction was stirred at ambient temperature for 5hours. The reaction was cooled in an ice bath and saturated NH₄ Cl (25ml) was added. The mixture was extracted with EtOAc, and the EtOAcextract was washed with H₂ O, dried with Na₂ SO₄ and concentrated toyield 5.0 g of a white solid. The product was recrystallized from EtOActo yield 3.8 g of white crystalline flakes. The compound was dissolvedin anhydrous Et₂ O (200 ml) and MeOH (20 ml) and the insolubles werefiltered away. The filtrate was acidified with ethereal HCl toprecipitate the salt. Additional anhydrous Et₂ O (200 ml) was added andthe suspension was stirred 15 minutes. The solid was collected to yield4.5 g of a white powder. Two recrystallizations from MeOH gave 2.2 g.The concentrated mother liquor from the MeOH recrystallizations (2.0 g)was recrystallized from DMF to afford 1.2 g. The two samples werecombined and a final recrystallization from MeOH provided 3.0 g (57%) ofa white powder m.p.=254-256° C.

ANALYSIS: Calculated for C₁₆ H₂₃ FN₄ O.HCl: 56.05% C 7.06% H 16.34% N;Found: 55.99% C 6.99% H 16.27% N

EXAMPLE 201N-[2-[4-(6-Fluoro1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-aminophthalimidefumarate

A solution containing2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]amine (6.8 g,25.7 mmol), dicyclohexyl carbodiimide (DCC, 8.2 g, 39 mmol) and4-aminophthalic acid (4.57 g, 25.2 mmol) in dimethylformamide (DMF, 100ml) was heated at 110° C. for 5 hours and kept at 65° C. for 18 hours.At the end of the reaction, the solids (DCU) were filtered and thesolvent was removed on a rotary evaporator using a vacuum pump. Theresulting crude product was purified by flash chromatography (SiO₂, 130g) and provided 7.5 g (83%) of the desired product. It was converted tothe fumarate salt which was recrystallized from ethanol and isopropylether: 7.1 g, m.p.=229-230° C.

ANALYSIS: Calculated for C₂₂ H₂₁ FN₄ O₃.C₄ H₄ O₄ : 59.54% C 4.80% H10.68% N; Found: 58.99% C 4.79% H 10.37% N

EXAMPLE 202N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6-pyrrolo-3,4-6]pyridine-5,7-dionefumarate

A solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (4.14 g,15.7 mmole) and 3,4-pyridinedicarboxylic anhydride (2.64 g, 17.7 mmol)in dimethylformamide (DMF, 100 ml) was heated at 130° C. for 18 hours.The solvent was removed on the rotary evaporator with a vacuum pump. Theresidue was dissolved into ethanol (250 ml) and the insolubles werefiltered. To the ethanol solution was added fumaric acid (1.82 g, 1.0eq), then the solution was concentrated to 120 ml. Isopropyl ether (120ml) was added and the mixture was stirred overnight. The white crystals(3.1 g, 48%), m.p.=203-206° C., were collected and recrystallized againfrom ethanol to give 2.34 g of pure product, m.p.=208-209° C.

ANALYSIS: Calculated for C₂₁ H₁₉ N₄ O₃.C₄ H₄ O₄ : 58.82% C 4.54% H10.98% N; Found: 58.59% C 4.67% H 10.71% N

EXAMPLE 203N-[2,3-Epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidinefumarate

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50mmol), K₂ CO₃ (7.5 g, 54 mmol) and epibromohydrin (9 g, 54 mmol) inacetonitrile (150 ml) was heated at reflux for 16 hours. The mixture wasfiltered and concentrated to dryness. The crude product was purified byflash chromatography (SiO₂, 180 g, eluted with methylene chloride (DCM),and 1-2% CH₃ OH in DCM). The material thus purified as off-white solidsweighed 8.7 g (63%). This material (3 g) was converted to fumarate saltin ethanol and isopropyl ether to give 3.27 g of white crystals,m.p.=145-147° C.

ANALYSIS: Calculated for C₁₅ H₁₇ FN₂ O₂.C₄ H₄ O₄ : 58.16% C 5.39% H7.14% N; Found: 57.93% C 5.35% H 7.02% N

EXAMPLE 2044-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propoxyphenylmethyl ether

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.4 g, 20mmol) and 2,3-epoxypropyl-4-methoxyphenylether (3.7 g, 20.5 mmol) inisopropyl alcohol (80 ml) was heated to reflux for 2 hours. The mixturewas cooled and the crystals were collected to yield 6.81 g (85%),m.p.=134-135° C.

ANALYSIS: Calculated for C₂₂ H₂₅ FN₂ O₄ : 65.99% C 6.29% H 7.00% N;Found: 66.11% C 6.31% H 6.84% N

EXAMPLE 2053-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propylphthalimide

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5.5 g, 25mmol) and N-(2,3-epoxypropyl)phthalimide (5.1 g, 25.5 mmol) inisopropanol (100 ml) was heated at reflux for 4 hours and stirred at 65°C. for 18 hours. The reaction was cooled and the solvent was removed ona rotary evaporator. The white solids were dissolved in methylenechloride and purified on a silica gel column (110 g, eluted with 1% CH₃OH in DCM, 1.5 l). The pure product thus obtained weighed 7.91 g, 75%.Recrystallization from DCM and isopropyl ether yielded 4.0 g,m.p.=162-163° C.

ANALYSIS: Calculated for C₂₃ H₂₂ FN₃ O₄ : 65.24% C 5.24% H 9.92% N;Found: 65.00% C 5.05% H 9.77% N

EXAMPLE 2061-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-phthalimido-2-propyldecanoate fumarate

To a solution of3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propylphthalimide(6.26 g, 14.5 mmol), triethylamine (2.0 g, 20 mmol) in chloroform (200ml) was charged with decanoyl chloride (3.6 g, 18.9 mmol, 1.26equivalent) dropwise at room temperature. The mixture was stirredovernight. The mixture was concentrated and the crude product waspurified on a flash chromatography column. The product thus obtained asan oil (4.96 g, 59%). This oil was converted to fumarate salt in adilute ethanol solution to yield 2.0 g, m.p.=138-140° C.

ANALYSIS: Calculated for C₃₃ H₄₀ FN₃ O₅.C₄ H₄ O₄ : 64.06% C 6.39% H6.06% N; Found: 63.90% C 6.39% H 5.88% N

EXAMPLE 207N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-4-methylphthalimidedihydrochloride

A solution of 2-[4-[(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]amine(1.9 g, 7.2 mmol), 4-methylphthalic anhydride (1.2 g, 7.4 mmol) and DMF(50 ml) was stirred at 75° C. for 5 hours. Most of the DMF was removedin vacuo and the resultant red oil was triturated with H₂ O to produce abrown solid. The product was dissolved in CH₂ Cl₂ and the organicextract was washed with H₂ O, dried with MgSO₄ and concentrated toafford 2.8 g of a foam. The compound was suspended in MeOH (50 ml) andmade acidic with ethereal HCl and the resultant solution was stirred for1 hour. Anhydrous Et₂ O was added to precipitate 2.5 g of an off-whitepowder. This was combined with an additional sample (4.3 g total), andtwo recrystallizations from MeOH-Et₂ O provided 3.0 g (56%) of anoff-white powder, m.p.=238-241 ° C.

ANALYSIS: Calculated for C₂₂ H₂₂ Cl₂ FN₅ O₂.2HCl: 55.01% C 5.04% H14.58% N; Found: 55.35% C 5.09% H 14.56% N

EXAMPLE 208N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-4-fluorophthalimidehydrochloride

A solution of 2-[4-[(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]amine(4.0 g, 15 mmol), 4-fluorophthalic anhydride (2.5 g, 15 mmol) and DMF(75 ml) was stirred at 75° C. under N₂ for 4 hours. The reaction wasconcentrated to yield 6.7 g of a brown solid. The product was suspendedin MeOH (150 ml) and was acidified with ethereal HCl. After stirring for30 minutes, anhydrous Et₂ O was added and the resultant beige solid wascollected to yield 5.1 g. The compound was recrystallized fromMeOH-ether to give 3.8 g (56%) of an off-white powder, m.p.=282-285° C.

ANALYSIS: Calculated for C₂₁ H₁₉ F₂ N₅ O₂.HCl: 56.32% C 4.50% H 15.64%N; Found: 56.07% C 4.35% H 15.63% N

EXAMPLE 209N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-(1-decanoyl)aminophthalimide

To a solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-aminophthalimide(1.5 g, 3.67 mmol), triethylamine (0.46 mg, 4.6 mmol) in chloroform (30ml) was charged with decanoyl chloride (0.8 mg, 4.2 mmol) dropwise atroom temperature. The mixture was stirred for 1 hour. An additionalportion of decanoyl chloride (0.1 mg, 0.52 mmol) was added to completethe reaction. The mixture was concentrated down, and the crude productwas purified on a flash chromatography column (30 g of silica gel;eluted with dichloromethane (DCM) and 1% CH₃ OH in DCM). The oilyproduct was dissolved in ethanol and treated with ether to yield whitecrystals 1.04 g (47.5%), m.p.=159-160° C.

ANALYSIS: Calculated for C₃₂ H₃₉ N₄ O₄ : 68.31% C 6.99% H 9.96% N;Found: 68.47% C 7.27% H 9.95% N

EXAMPLE 210N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-(1-decanoyl)oxyphthalimidefumarate

To a mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]ethyl]-4-hydroxyphthalimide(5.1 g, 12.5 mmol), triethylamine (2.09 g, 1.67 equiv) in chloroform(150 ml) was charged decanoyl chloride (3.8 g, 20 mmol) dropwise at roomtemperature. The mixture was stirred at room temperature overnight (16hours). The solution was diluted with methylene chloride (DCM, 150 ml)and washed with brine. The organic solution was dried and concentratedto a crude mixture. Purification on a flash chromatography column (SiO₂,100 g, eluted with DCM and 1% CH₃ OH in DCM) yielded a colorless oil(5.0 g, 71%). This product was treated with fumaric acid (1.0 g) inethanol (30 ml) and isopropyl ether (15 ml) to give 3.1 g of whitecrystals, m.p.=108-110° C.

ANALYSIS: Calculated for C₃₂ H₃₈ FN₃ O₅.C₄ H₄ O₄ : 63.61% C 6.23% H6.18% N; Found: 63.71% C 6.30% H 6.25% N

EXAMPLE 2112-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl-2,3-dihydro-3-hydroxy-1H-isoindol-1-onehemifumarate

To a stirred suspension ofN2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-phthalimide(4.0 g, 10 mmol) in MeOH (125 ml) and CH₂ Cl₂ (15 ml) under N₂, wasadded NaBH₄ (0.89 g, 23 mmol) in one portion. The reaction was stirredat ambient temperature for 45 minutes and was concentrated to yield adamp white solid. Flash chromatography using silica gel and 5% MeOH-CH₂Cl₂ increasing to 10% MeOH-CH₂ Cl₂ as eluent, provided 4.5 g of a beigeliquid. The liquid was dissolved in MeOH (50 ml), and the solution wasacidified with ethereal HCl. Anhydrous Et2O was added to precipitate 2.9g of a white solid. This was combined with an additional sample (4.6 gtotal) and was suspended in H₂ O (100 ml). NaHCO₃ was added to attainpH˜7 and the gummy mixture was extracted with CH₂ Cl₂. The CH₂ Cl₂extract was dried with MgSO₄ and concentrated to yield 4.1 g of a whitefoam. The compound was purified by preparative HPLC (Water's AssociatesPrep LC/System 500, using 2 silica gel columns and 5% Et₂ NH-EtOAc aseluent). Concentration of appropriate fractions gave 2.1 g (5.3 mmol) ofa beige foam. The compound was dissolved in EtOAc (50 ml) and theinsolubles were filtered away. The filtrate was gently warmed andfumaric acid (0.70 g, 6.0 mmol) was added. After stirring at mild refluxfor 30 minutes and at ambient temperature for 1 hour, the mixture wasdiluted with anhydrous Et₂ O (50 ml).

The resultant solid was collected and dried to yield 2.2 g.Recrystallization from ethanol-ether provided 1.1 g (16%) of thehemi-fumarate salt as a slightly off-white solid m.p.=165-168° C.

ANALYSIS: Calculated for C₂₁ H₂₂ FN₅ O₂.0.5C₄ H₄ O₄ : 60.91% C 5.35% H15.45% N; Found: 60.41% C 5.15% H 15.22% N

EXAMPLE 2124-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propoxyl-3-methoxyphenylmethanone

A stirred mixture of 4-(2,3-epoxypropoxy)-3-methoxyphenyl methanone (4.5g, 22.5 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5.36 g,24.3 mmol) in isopropyl alcohol (150 ml) was heated at 55° C. for 16hours. The mixture was cooled and the solvent was removed on a rotaryevaporator. The residue was purified by flash chromatography over asilica gel column (SiO₂, 80 g; eluted with dichloromethane, DCM, and 1%CH₃ OH in DCM). The oil thus obtained solidified quickly, weight: 9.47g. Recrystallization from ethanol and isopropyl ether, then tolueneprovided 8.6 g (86%) of white crystals, m.p.=107-108° C.

ANALYSIS: Calculated for C₂₄ H₂₇ FN₂ O₅ : 65.15% C 6.15% H 6.33% N;Found: 65.35% C 6.04% H 6.05% N

EXAMPLE 2131-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-propanonehydrochloride

A mixture of 4-(6fluoro-1,2-benzisoxazol-3-yl)piperidine (7.45 g, 33.4mmol), K₂ CO₃ (5.5 g) and bromo-2,2-dimethoxypropane (6.84 g, 37.6 mmol)in acetonitrile (200 ml) was heated and stirred at reflux for 4 hours.An additional charge of bromo-2,2-dimethoxypropane (5.1 g, 28 mmol) wasadded and the mixture was refluxed overnight. After being cooled to roomtemperature, the mixture was filtered, and the solvent was removed on arotary evaporator. The residue was purified by flash chromatography overa silica gel column (SiO₂, 100 g; eluted with dichloromethane, DCM, and1% CH₃ OH in DCM). The oil product thus obtained weighed 2.2 g (24%).The oil product was dissolved into ethanol (10 ml) then was treated withHCl in ether solution (1M, 9 ml) at room temperature. The crystals werecollected, 2.08 g, m.p.=220-223° C. dec.

ANALYSIS: Calculated for C₁₅ H₁₇ FN₂ O₂.HCl: 57.60% C 5.80% H 8.96% N;Found: 57.49% C 5.97% H 8.67% N

EXAMPLE 2141-[(4-Aceto-2-methoxy)phenoxy]-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-propyldecanoate fumarate

To a stirred mixture of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propoxy]-3-methoxyphenylmethanone (3.64 g, 8.23 mmol), triethylamine (1.6 g, 16 mmol) inchloroform (150 ml) was added decanoyl chloride (2.35 g, 12.4 mmole, 1.5eq) dropwise at room temperature. The mixture was then heated at refluxfor 1 hour. The mixture was cooled and diluted with methylene chloride(DCM) and washed with water and brine. The organic solution was driedand concentrated to a crude mixture. Purification on a flashchromatography column (SiO₂, 65 g; eluted with DCM, 0.4l and 1% CH₃ OHin DCM, 0.6l) yielded a colorless oil: 3.29 g (67%). This product wastreated with fumaric acid (623 mg) in ethanol (10 ml) and isopropylether (50 ml) to give 2.64 g of a white solid, m.p.=109-110° C.

ANALYSIS: Calculated for C₃₄ H₄₅ FN₂ O₆.C₄ H₄ O₄ : 64.03% C 6.93% H3.93% N; Found: 63.86% C 6.88% H 3.74% N

EXAMPLE 215N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]thiaphthalimide

A mixture ofN-[2-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]ethyl]-phthalimide(3.93 g, 10 mmol) and2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadephosphetane-2,4-disulfide (2.02g, 5 mmol, 1 equiv. Lawesson's Reagent) is stirred and heated inanhydrous tetrahydrofuran for 3 hours at 60° C. The reaction mixture isevaporated on silica gel and purified by chromatography on a silica gelcolumn. The product is further purified by recrystallization to affordN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]thiaphthalimide.

EXAMPLE 216

By using substantially the same procedure as described in Example 215except that 10 mmol (2 equiv.) of Lawesson's Reagent is used and thereaction time at 60° C. is extended to 5 hours there is obtainedN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-1,3-bis-thiaphthalimide.

EXAMPLE 217N-[2-[4-(6-Fluoro-1-decanoyl-1H-indazol-3-yl)-1-piperazinyl]-ethyl]phthalimidemaleate

To a stirred suspension of NaH (0.50 g of a 50% oil dispersion, 12.5mmol) in DMF (10 ml) under N₂ and cooled to -15° C., was added dropwise,N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide (4.0g, 10.2 mmol) dissolved in DMF (45 ml) over 45 minutes so that thetemperature did not exceed -8° C. The reaction was stirred for 1 hourallowing the temperature to warm to 0° C. The reaction was cooled to-12° C. and a solution of decanoyl chloride (2.9 g, 15.3 mmole) in DMF(13 ml) was added dropwise so that the temperature remained below -5° C.After complete addition, the reaction was stirred at ambient temperaturefor 18 hours. The reaction was poured into ice-cold H₂ O (125 ml) andthe aqueous mixture was extracted with EtOAc. The EtOAc extract waswashed with H₂ O/Brine (3×), dried with MgSO₄ and concentrated to yield5.7 g of a beige oil that readily crystallized. This was combined withanother sample (6.4 g total) and purification via flash chromatography,over silica gel using 3% MeOH/CH₂ Cl₂ as eluent, afforded 4.9 g (78%) ofa white solid. Another previously purified sample was combined with this(6.3 g, 11.5 mmol total) and the product was dissolved in hot absoluteethanol (100 ml). Maleic acid (1.4 g, 12.1 mmole) was added and thesolution was stirred at a mild reflux for 30 minutes. The reaction wasconcentrated to a white slush that was diluted with petroleum ether (100ml) and stirred for ca 2 hours. The resultant solid was collected toyield 5.5 g of shiny white crystals. The salt was recrystallized twicefrom absolute ethanol to afford 4.3 g and a third recrystallization fromCH₃ CN gave 3.8 g (39%) of the analytically pure maleate salt as a whitesolid, m.p.=154-156° C.

ANALYSIS: Calculated for C₃₁ H₃₈ FN₅ O₃.C₄ H₄ O₄ : 63.34% C 6.38% H10.55% N; Found: 63.46% C 6.33% H 10.60% N

EXAMPLE 2182-[4-[6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]aminedihydrochloride hemihydrate

(A) 2-[4-[6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionitrile

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidine (10 g, 45.4mmol); 2-chloropropionitril (10 g, 112 mmol), K₂ CO₃ (9.4 g, 1.5 eq) inacetonitrile (100 ml) was stirred and heated at 80° C. for 16 hours. Themixture was filtered and concentrated to dryness. The crude solids werepurified by flash chromatography (SiO₂, 160 g; eluted with methylenechloride, (DCM) 1.5 l; and 1% CH₃ OH in DCM, 1 l). The white solidmaterial thus obtained weighed 10.1 g and was recrystallized fromethanol and isopropyl ether to yield 5.1 g, m.p.--133-134° C.

ANALYSIS: Calculated for C₁₅ H₁₆ FN₃ O: 65.92% C 5.90% H 15.37% N;Found: 65.92% C 5.85% H 15.52% N

(B) 2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]aminedihydrochloride hemihydrate

To a solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionitrile (6.7g, 24.5 mmol) in THF (200 ml) was added lithium aluminum hydride (3.6 g,50% in oil, 2 eq) in portions under N₂ at room temperature for 3.5hours. At the end of the reaction, the excess of LAH was carefullyhydrolyzed with ice-chips (7 ml) under N₂. A solution of 15% NaOH (2 ml)was added, then the mixture was stirred for 30 minutes. The insolubleswere filtered and the organic solution was concentrated down to a paleoil (7.6 g) which partially solidified. A sample (1.5 g) of this mixturewas dissolved into ethanol and was treated with Hcl (6 ml, 1M in ether).The white solid which precipitated was collected and recrystallized fromethanol to give 708 mg, m.p. 215-217° C. of the dihydrochloridehemihydrate.

ANALYSIS:

Calculated for C₁₅ H₂₀ FN₃ O.2HCl.0.5H₂ O: 50.14% C 6.45% H 11.69% N2.50% H₂ O; Found: 49.94%c 6.17% H 11.11% N 2.12% H₂ O

EXAMPLE 219N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]phthalimidehydrochloride

To a stirred mixture of2-[4-[(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propyl]amine 2.56g, 9.2 mmol) and triethylamine (1.35 g, 13.5 mmol) in chloroform (150ml) was added phthalic anhydride (1.61 g, 10.9 mmol). The mixture wasstirred at room temperature for 4 hours. At the end of the reaction thesolvent was evaporated on a rotary evaporator and the crude residue wasdried in vacuo. The purification was done by flash chromatography over asilica gel column (40 g, SiO₂, eluted with methylene chloride, thenincrease the MeOH concentration to 2%). The pure product thus obtained(2.18 g) was combined with another batch of same quality material (1.53g) and then was converted to the hydrochloride salt with HCl in ethersolution. The white solid was recrystallized from methanol to give 3.12g, m.p.=275-277° C.

ANALYSIS:

Calculated for C₂₃ H₂₂ FN₃ O₃.HCl: 62.23% C 5.22% H 9.47% N; Found:61.93% C 5.32% H 9.46% N

EXAMPLE 220N-[2-[4-(1-Decanoxycarbonyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-phthalimidehydrochloride

A mixture of decanyl chloroformate (2.4 g, 11 mmol), andN-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide (3.9g, 10 mmol) was warmed on the steam bath for 15 minutes. The reactionwas allowed to cool to ambient temperature, and then ether was added tothe residue. The resulting solid was filtered to affordN-[2-[4-(1-decanoxy-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimidehydrochloride.

EXAMPLE 221N-[2-[4-(6-Fluoro1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-methoxyphthalimidehydrochloride

A mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-hydroxyphthalimidehydrochloride (4.36 g, 10.33 mmol) and K₂ CO₃ (3.6 g, 26 mmol) inmethanol was stirred for 15 minutes. Then dimethylsulfate (4.0 g, 3.17mmol) was added, followed by potassium t-butoxide (1.1 g, 10 mmol) andthe mixture was stirred at room temperature for 4 hours. The reactionmixture was concentrated and the residue was extracted with DCM (400ml). The organic layer was filtered and concentrated and the resultingresidue was chromatographed on silical gel (47 g SiO₂), eluting with DCMand MeOH:DCM mixture. The resulting product (1.4 g) was converted to thehydrochloride salt in ethanol with 1N-HCl in ether. The resulting whitesolid was recrystallized from methanol to give 1.12 g, mp=247-250° C.

ANALYSIS: Calculated for C₂₃ H₂₂ FN₃ O₄.HCl: 60.07% C 5.04% H 9.14% N;Found: 59.79% C 5.05% H 8.98% N

EXAMPLE 2226-Fluoro-3[-1-[3-(2,5-dimethoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazolehydrochloride

(A) 2-(3-Chloropropoxy)-1,4-dimethoxybenzene

A mixture of 2,5-dimethoxyphenol (29 g, 0.19 mol), K₂ CO₃ (35 g),3-chlorobromopropane (38.5 g, 0.25 mol) and acetone (250 ml) was stirredand refluxed for 6 hours, and then stirred at ambient temperature for 16hours. The reaction was filtered, and the filtrate was concentrated toan orange liquid. The liquid was taken up into Et₂ O, and the organiclayer washed with 1N NaOH, H₂ O, dried (MgSO₄) and was concentrated toyield 37.8 g of an orange solid. An 11.7 g sample of this solid wasflash chromatographed on silica gel (180 g) with 5% EtOAc/CH₂ Cl₂ aseluent. Concentration of similar fractions gave 7.2 g of white, waxysolid, which was recrystallized from petroleum ether to afford a whitesolid, m.p. 48-50° C.

ANALYSIS: Calculated for C₁₁ H₁₅ ClO₃ : 57.27% C 6.55% H; Found: 57.19%C 6.52% H

(B)6-Fluoro-3-[1-[3-(2,5-dimethoxyphenoxy)propyl]-4-piperidinyl]-1,2-benzisoxazoleHydrochloride

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 14.0mmol), 2-(3-chloropropoxy)-1,4-dimethoxybenzene, K₂ CO₃ (2.1 g) andacetonitrile (50 mL) was stirred and refluxed for 24 hours. The reactionwas filtered and the filtrate was concentrated to 5.0 g of an oil. Theoil was chromatographed on a preparative HPLC on a silica gel columnwith 5% MeOH-CH₂ Cl₂ as eluent. Concentration of the appropriatefractions afforded 4.6 g of an oil, which, with ethereal HCl, wasconverted to 4.0 g of a white hydrochloride salt. The salt wasrecrystallized twice from EtOH to yield 2.9 g of product as a whitesolid, m.p. 186-188° C.

ANALYSIS: Calculated for C₂₃ H₂₇ FN₂ O₄.HCl: 61.26% C 6.26% H 6.21% N;Found: 61.14% C 6.38% H 6.15% N

EXAMPLE 2234-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-2-hydroxy-5-methoxy-alpha-methylbenzenemethanol

(A). 1-[4-(3-Chloropropoxy)-2-hydroxy-5-methoxyphenyl]ethanone

A mixture of 2,4-dihydroxy-5-methoxyacetophenone (1.4 g, 7.7 mmol), K₂CO₃ (1.4 g, 10.0 mmol), 3-chlorobromopropane (1.6 g, 10.0 mmol) andacetone (25 mL) was stirred and refluxed under N₂ for 16 hours. Thereaction was poured into H₂ O, and the aqueous suspension was extractedwith ethyl acetate. The extract was washed (H₂ O, brine) dried (MgSO₄)and concentrated to yield 1.4 g of an off-white solid. Recrystallizationtwice from ethanol afforded 0.4 g of the alkylated phenol as a solid,m.p. 99-101° C.

ANALYSIS: Calculated for C₁₂ H₁₅ ClO₄ : 55.71% C 5.84% H; Found: 55.61%C 5.92% H

(B)1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-2-hydroxy-5-methoxyphenyl]ethanone

A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.2 g, 19mmol), 1-[4-(3-chloropropoxy)-2-hydroxy-5-methoxyphenyl]ethanone (5.0 g,19 mmol), NaHCO₃ (1.8 g, 20 mmol) and acetonitrile (120 mL) was stirredand refluxed for 16 hours. The reaction was filtered and the filtratewas concentrated to a dark oil. The oil was taken up in anhydrous etherand ethereal HCl was added to precipitate 8.7 g of an off-whitehydrochloride salt. A 2.0 g sample of the salt was converted to its freebase and chromatographed by preparative HPLC (silica gel with 5%MeOH/CH₂ Cl₂ as eluent). Concentration of the desired fractions gave 1.1g of a white solid, which was recrystallized from EtOH to yield 0.85 gof the product, m.p. 122-124° C.

ANALYSIS: Calculated for C₂₄ H₂₇ FN₂ O₅ : 65.15% C 6.15% H 6.33% N;Found: 64.93% C 6.23% H 6.20% N

(C)4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-2-hydroxy-5-methoxy-alpha-methylbenzenemethanol

To a stirred solution of4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-5-methoxyphenyl]ethanone(3.0 g, 6.8 mmol) in tetrahydrofuran/ethanol (70 ml, 4:3) was addedsodium borohydride (0.26 g, 6.8 mmol). The reaction was stirred atambient temperature for 0.75 hours, and then concentrated to afford athick oil. The oil was triturated with H₂ O and the aqueous suspensionwas extracted with CH₂ Cl₂. The extract was washed with H₂ O, dried(MgSO₄) and concentrated to afford 3.4 g of a white solid. The solid wasrecrystallized from MeOH and then from EtOH to yield 0.80 g of solid,m.p. 156-158° C.

ANALYSIS: Calculated for C₂₄ H₂₉ FN₂ O₅ : 64.85% C 6.58% H 6.30% N;Found: 64.73% C 6.58% H 6.13% N

EXAMPLE 224N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimidefumarate

A solution of fumaric acid (448 mg, 3.86 mmol) in ethanol was added to ahot solution of2-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]ethyl]phthalimide(1.52 g, 3.86 mmol) in ethanol. The solution was cooled and the crystalswere collected to yield 1.9 g. Recrystallization once from ethanolyielded 1.15 g of the fumarate salt, m.p. 231-232° C.

ANALYSIS: Calculated for C₂₂ H₂₀ FN₃ O₃.C₄ H₄ O₄ : 61.29% C 4.75% H8.25% N; Found: 61.03% C 4.68% H 8.38% N

EXAMPLE 225N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimide

(A) 1-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxybutane

A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5.5g, 25 mmol) and 1,2-expoxybutane (1.89 g, 26.3 mmol) in isopropylalcohol (100 ml) was heated at 65° C. for 2 days. This mixture wascooled and the solvent was removed to leave a brown oil which waspurified by flash chromatography over a silica gel column (SiO₂, 70 g;eluted with DCM, 1 l and MeOH:DCM 2%: 98%) to give an off-white solidweighing 6.3 g. Recrystallization from hot ethanol yielded 1.96 g offine crystals, m.p. 87-88° C.

ANALYSIS: Calculated for C₁₆ H₂₁ FN₂ O₂ : 65.73% C 7.24% H 9.58% N;Found: 65.83% C 7.12% H 9.54% N

(B)N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimide

A solution of diethyl azodicarboxylate (DEAD, 4.9 g, 28.3 mmol) in THF(50 ml) was added dropwise to a solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (6.9 g, 23.6mmol), phthalimide (4.16 g, 1.2 eq), and triphenylphosphine (7.4 g, 28.3mmol) in THF (200 ml) at room temperature. The solution was stirred atroom temperature for 24 hours. After the reaction, the solvent wasstripped to dryness. The residue was stirred in ether (200 ml) and theinsolubles were removed by filtration. The oily residue fromconcentration of the ether solution was purified by two flashchromatography (SiO₂, 75 g, eluted with dichloromethane, DCM, and 1-2%CH₃ OH in DCM) and (100 g of SiO₂ ; eluted with DCM, 1 l, and 1% CH₃ OHin DCM, 1.2 l). Two close compounds were separated and the top compoundon TLC (1.6 g) was recrystallized from isopropyl ether to yield 0.76 gof white crystals, m.p. 86-88° C.

ANALYSIS: Calculated for C₂₄ H₂₄ FN₃ O₃ : 68.39% C 5.74% H 9.97% N;Found: 68.47% C 5.67% H 9.97% N

EXAMPLE 226N-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butyl]phthalimidehydrochloride

A solution of diethyl azodicarboxylate (DEAD, 4.9 g, 28.3 mmol) in THF(50 ml) was added dropwise to a solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butanol (6.9 g,23.6 mmol), phthalimide (4.16 gm, 1.2 eq), and triphenylphosphine (7.4g, 28.3 mmol) in THF (200 ml) at room temperature. The solution wasstirred at room temperature for 24 hours. After the reaction, thesolvent was stripped and the residue was stirred in ether (200 ml). Theinsolubles were removed by filtration. The oily residue fromconcentration of the ether solution was purified by two flashchromatography (SiO₂, 75 g; eluted with dichloromethane, DCM, and 1-2%CH₃ OH in DCM) and SIO₂, 100 g; eluted with DCM, 1 l; and 1% CH₃ OH inDCM, 1.2 l). Two close compounds were separated. The lower compound onTLC 3.66 g) was treated with HCl/ether in ethanol, and the solid saltwas precipitated with hexane. Recrystallization from ethanol andisopropyl ether yielded white crystals 3.26 g, m.p. 210-214° C. dec.

ANALYSIS: Calculated for C₂₄ H₂₄ FN₃ O₃.HCl: 62.95% C 5.50% H 9.18% N;Found: 62.70% C 5.58% H 9.13% N

EXAMPLE 2274-Fluoro-N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimidemaleate

(A) 1-Benzoyl-6-fluoro-3-(1-phenoxycarbonyl-4-piperidinyl)-1H-indazole

To a solution of1-benzoyl-6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole (2.0 g, 5.93mmol) in dichloromethane (100 ml) was added phenyl chloroformate (3.9ml, 29.65 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 24 hours, refluxed for an additional 0.5 hours andsubsequently concentrated. The remaining residue was dissolved intodichloromethane and washed with 10% HCl (aq.). The organic phase wasdried (MgSO₄), filtered, and concentrated to give an oil which waspurified via flash column chromatography (silica gel, 20% DCM/EtOAc).Concentration of the product-containing fractions gave an oil whichsolidified on standing. The white solid was washed with EtOAc, leaving0.47 g of the desired product, m.p. 137-139° C.

ANALYSIS: Calculated for C₂₆ H₂₂ FN₃ O₃ : 70.42% C 5.00% H 9.48% N;Found: 70.38% C 4.81% H 9.42% N

(B) [4-(6-Fluoro-1H-indazol-3-yl)-1-piperidinyl]acetonitrile

To a suspension of1-benzoyl-6-fluoro-3-(1-phenoxycarbonyl-4-piperidinyl)-1H-indazole (31.6g, 71.3 mmol) in ethanol (500 ml) was added 50% KOH(aq.) (100 g of KOHin 100 g H₂ O) at room temperature. The reaction mixture was warmed toreflux for 4 hours and cooled to room temperature. After adjusting thepH to about one (to litmus) using HCl (con., 110 ml), the volatiles wereremoved under reduced pressure. The remaining wet solid was diluted withwater and collected via filtration. The solid material was dissolvedinto hot water to which 50% NaOH(aq.) was added (pH was about 10, tolitmus). The precipitated 4-(6-fluoro-1H-indazol-3-yl)piperidine (10.7g) was filtered and used without further purification.

To a stirred suspension of 4-(6-fluoro-1H-indazol-3-yl)piperidine (4.95g, 22.6 mmol) and NaHCO₃ (2.1 g, 24.9 mmol) in dry acetonitrile (110 ml)was added chloroacetonitrile (1.6 ml, 24.9 mmol) at room temperature,under nitrogen. The suspension was warmed to reflux for 22.5 hours,cooled to room temperature, and subsequently filtered. The remainingsolids were washed with DCM and the combined filtrates wereconcentrated. The resulting brown oil was dissolved into EtOAc andwashed with water. The organic phase was dried (MgSO₄), filtered andconcentrated to give a brown solid which was re-dissolved into DCM/EtOAcand flushed through alumina with DCM. The eluent was concentrated togive 5.2 g of the desired product as a solid, m.p. 149-151° C.

ANALYSIS: Calculated for C₁₄ H₁₅ FN₄ : 65.10% C 5.85% H 21.69% N; Found:64.84% C 5.90% H 21.74% N

(C). 2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperidinyl]ethylamine

To a solution of[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]-acetonitrile (6.1 g, 23.6mmol) in dry THF (235 ml) was added (dropwise) lithium aluminum hydride(LAH) (28.4 mmol, 1.0M in THF) at room temperature, under nitrogen. Uponcomplete addition, the reaction mixture was warmed to reflux for 3hours. After cooling to 0° C. in an ice bath, the reaction was carefullyquenched with water (4.0 ml). The solids were removed via filtration andwashed with THF. The combined filtrates were concentrated to give 5.6 gof the desired product. This material was suspended in DCM and filteredto give the product as an off-white solid, m.p. 125-128° C.

ANALYSIS: Calculated for C₁₄ H₁₉ FN₄ : 64.10% C 7.30% H 21.36% N; Found:63.60% C 7.10% H 21.03% N

(D).4-Fluoro-N-[2-(4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]-phthalimidemaleate

To a solution of 2-[4-(6-fluoro-1H-3-indazolyl)-1-piperidinyl]ethylamine(6.1 g, 23.3 mmol) in DMF (230 ml) was added 4-fluorophthalic anhydride(4.2 g, 25.5 mmol) at room temperature under nitrogen. The reactionmixture was warmed to 80° C. for 2.5 hours at which time it was allowedto cool to room temperature. The DMF was removed under reduced pressureto give a brown oil which was dissolved into DCM/MeOH. Purification viaflash column chromatography (silica gel, 2% MeOH/DCM) afforded 3.6 g ofthe desired product as a white solid. The maleate salt was prepared inmethanol (75 ml) using maleic acid (2.1 eq.). The precipitated salt wascollected via filtration and recrystallized from acetonitrile to give awhite solid, m.p. 193-195° C.

ANALYSIS: Calculated for C₂₂ H₂₀ F₂ N₄ O₂.C₄ H₄ O₄ : 59.31% C 4.59% H10.64% N; Found: 59.15% C 4.80% H 10.80% N

EXAMPLE 228N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-3-methylphthalimidehydrochloride

A solution of 2-[4-[(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethylamine(5.9 g, 22.4 mmol), 3-methyphthalic anhydride (3.7 g, 22.5 mmol) and DMF(120 ml) was stirred at 85° C. for 22 hours under N₂. Most of the DMFwas distilled off to afford 12.5 g of a dark oil. The oil was purifiedby preparative HPLC (Waters Associates Prep 500 using 2 silica gelcolumns and 4% MeOH-CH₂ Cl₂ as eluent) to yield 6.4 g of a yellow foam.A 1.0 g sample was suspended in MeOH (25 ml) and the mixture was madeacidic with ethereal HCl. After about 20 minutes the resultant solutionwas filtered and the filtrate was diluted with anhydrous Et₂ O toprecipitate the salt. The light yellow solid was collected to give 0.90g which was triturated with boiling CH₃ CN (40 ml) and after cooling theproduct was collected to provide 0.75 g of a white solid, m.p. 266-269°C.

ANALYSIS: Calculated for C₂₂ H₂₂ FN₅ O₂.HCl: 59.53% C 5.22% H 15.78% N;Found: 59.31% C 4.98% H 15.77% N

EXAMPLE 229N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]propyl]phthalimidehydrochloride

A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (7.0 g, 31.8 mmol),NaHCO₃ (2.9 g, 34.5 mmol), N-(3-bromopropyl)phthalimide (8.5 g, 31.8mmol) and acetonitrile (200 ml) was stirred at reflux under N₂ for 21hours. Most of the acetonitrile was removed in vacuo and the resultantyellow residue was triturated with H₂ O to afford a solid. The productwas isolated by filtration and dried to yield 12.7 g. Recrystallizationfrom EtOH gave 7.8 g of a yellow solid. A 2.0 g sample was suspended inMeOH (25 ml) and the pH was adjusted to pH˜1 with ethereal-HCl. After 30minutes of stirring at ambient temperature, the thick suspension wasdiluted with isopropyl ether (10 ml) and Et₂ O (50 ml) and the saltcollected to yield 1.9 g. Recrystallization from EtOH provided 1.4 g(38%) of a light yellow solid, m.p. 261-264° C.

ANALYSIS: Calculated for C₂₂ H₂₂ FN₅ O₂.HCl: 59.53% C 5.22% H 15.78% N;Found: 59.48% C 5.25% H 15.56% N

EXAMPLE 2304-Fluoro-N-[2-[4-(1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimidemaleate

(A) 1-Benzenesulfonyl-3-(1-phenoxycarbonyl-4-piperazinyl)-1H-indazole

To a solution of1-benzenesulfonyl-3-(1-methyl-4-piperazinyl)-1H-indazole (2.1 g, 5.89mmol) in dichloromethane (100 ml) was added phenyl chloroformate (3.8ml, 29.45 mmol) at room temperature. The reaction mixture was warmed toreflux for 2 hours, cooled to room temperature, and concentrated. Theresidue was diluted with ethyl acetate, filtered and purified via flashcolumn chromatography (silica gel, ethyl acetate). Concentration of theproduct containing fractions gave an oil which solidified on standing.The product was washed well with heptane to give 1.5 g of a white solid,m.p. 112-114° C.

ANALYSIS: Calculated for C₂₄ H₂₂ N₄ O₄ S: 62.32% C 4.79% H 12.11% N;Found: 62.28% C 4.73% H 12.15% N

(B) [4-(1H-Indazol-3-yl)-1-piperazinyl]acetonitrile

To a suspension of1-benzenesulfonyl-3-(1-phenoxycarbonyl-4-piperazinyl)-1H-indazole (31.3g, 67.7 mmol) in ethanol (500 ml) was added 50% KOH (aq.) (100 g of KOHin 100 g H₂ O) at room temperature. The reaction mixture was warmed toreflux for 6.5 hours and cooled to room temperature. After adjusting thepH to about two using HCl (con., 120 ml), the volatiles were removedunder reduced pressure. The remaining residue was diluted with water andremoved via filtration. The aqueous filtrate was washed with EtOAc andbasified to pH=8 using 50% NaOH (aq.). The product was extracted into10:1 dichloromethane/isopropylalcohol. The combined organics were dried(MgSO₄), filtered, and concentrated to give 13.0 g of desired3-piperazin-1-yl-1H-indazole as a brown solid which was used withoutfurther purification.

To a stirred suspension of 3-piperazin-1-yl-1H-indazole (6.0 g, 29.7mmol) and NaHCO₃ (2.7 g, 32.7 mmol) in dry acetonitrile (125 ml) wasadded chloroacetonitrile (2.1 ml, 31.2 mmol) at room temperature, undernitrogen. The suspension was warmed to reflux for 17.5 hours, cooled toroom temperature, and subsequently filtered. The remaining solids werewashed with dichloromethane and the combined filtrates wereconcentrated. The resulting brown oil was purified via flash columnchromatography (silica gel, 0-50% EtOAc/DCM) to give 4.0 g of product asan off-white solid, m.p. 121-123° C.

ANALYSIS: Calculated for C₁₃ H₁₅ N₅ : 64.71% C 6.27% H 29.02% N; Found:64.47% C 6.23% H 28.82% N

(C) 4-Fluoro-N-[2-[4-(1H-indazol-3-yl)-1-piperazinyl]ethyl]-phthalimidemaleate

To a solution consisting of[4-(1H-indazol-3-yl)-1-piperazinyl]acetonitrile (8.7 g, 36.1 mmol) intetrahydrofuran (360 ml) was added lithium aluminum hydride (dropwise,43.3 ml of a 1.0M solution in tetrahydrofuran, 43.3 mmol) at roomtemperature, under nitrogen. The reaction mixture was warmed to refluxfor 3 hours at which time it was allowed to cool to room temperature.The reaction was carefully quenched with water (3.5 ml) and theprecipitated salts were removed via filtration and washed with EtOAc.The combined filtrates were concentrated to give a solid. This materialwas suspended in ether (4 days) and collected via filtration to give 4.7g of 2-[4-(1-indazol-3-yl)-1-piperazinyl]ethylamine which was usedwithout further purification.

A solution of intermediate2-[4-(1-indazol-3-yl)-1-piperazinyl]ethylamine (1.0 g, 4.1 mmol) and4-fluorophthalic anhydride (0.75 g, 4.5 mmol) in dimethylformamide (40ml) was warmed to 80° C. for 4 hours. After cooling to room temperature,the dimethylforamide was removed in vacuo (<0.5 mmHg, 55° C.) to give abrown oil which solidified on standing. The solid material was suspendedin EtOAc and warmed to reflux for 3 hours. The desired product remainedas a yellow solid (0.86 g) and was collected via filtration and driedunder high vacuum. The maleate salt was prepared in refluxing methanolusing maleic acid (0.53 g, 4.6 mmol). The off-white solid was collectedvia filtration and washed with methanol, m.p. 211-215° C.

ANALYSIS: Calculated for C₂₁ H₂₀ FN₅ O₂.C₄ H₄ O₄ : 58.94% C 4.75% H13.75% N; Found: 58.69% C 4.91% H 13.77% N

EXAMPLE 231N-[2-[4-(1-Decanoyl-6fluoro-1H-indazol-3yl)-1-piperazinyl]ethyl]-phthalimidemaleate

To a stirred suspension of NaH (0.50 g of a 60% oil dispersion, 12.5mmol) in dimethylformamide(DMF) (10 ml) under N₂ and cooled to -15° C.,was added dropwise,2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-1H-isoindol-1,3-(2H)-dione(4.0 g, 10.2 mmol) dissolved in DMF (45 ml) over 45 minutes so that thetemperature did not exceed -8° C. The reaction was stirred for 1 hourallowing the temperature to warm to 0° C. The reaction was cooled to-12° C. and a solution of decanoyl chloride (2.9 g, 15.3 mmol) in DMF(13 ml) was added dropwise so that the temperature remained below -5° C.After complete addition, the reaction was stirred at ambient temperaturefor 18 hours. The reaction was poured into ice-cold H₂ O (125 ml) andthe aqueous mixture was extracted with EtOAc. The EtOAc extract waswashed with H₂ O/brine, dried with MgSO₄ and concentrated to yield 5.7 gof a beige oil that readily crystallized. This was combined with anothersample (6.4 g total) and purification via flash chromatography, oversilica gel using 3% MeOH-CH₂ Cl₂ as eluent, afforded 4.9 g of a whitesolid. Another previously purified sample was combined with this (6.3 g,11.5 mmol total) and the product was dissolved in hot absolute ethanol(100 ml). Maleic acid (1.4 g, 12.1 mmol) was added and the solution wasstirred at a mild reflux for 30 minutes. The reaction was concentratedto a white slush that was diluted with petroleum ether (100 ml) andstirred for 2 hours. The resultant solid was collected to yield 5.5 g ofshiny white crystals. The salt was recrystallized twice from absoluteethanol to afford 4.3 g and a third recrystallization from CH₃ CN gave3.8 g of the maleate salt as a white solid, m.p. 154-156° C.

ANALYSIS: Calculated for C₃₁ H₃₈ FN₅ O₃.C₄ H₄ O₄ : 63.34% C 6.38% H10.55% N; Found: 63.46% C 6.33% H 10.60% N

EXAMPLE 232N-[2-[4-(1-Benzoyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-phthalimidehydrochloride

A mixture of2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-1H-isoindol-1,3-(2H)-dione(6.0 g, 15 mmol) and benzoyl chloride (25 ml) was stirred at 175° C.under N₂ for 2.0 hours. The reaction was cooled and diluted withanhydrous Et₂ O and the resultant hydrochloride salt was collected toyield 7.2 g. The compound was stirred in boiling absolute ethanol (300ml) for 1 hour and then at ambient temperature overnight. The solid wascollected and dried to afford 6.9 g. Recrystallization from MeOH gave3.9 g of a light grey solid, m.p. 257-260° C.

ANALYLSIS: Calculated for C₂₈ H₂₄ FN₅ O₃.HCl: 62.98% C 4.72% H 13.12% N;Found: 62.92% C 4.70% H 13.22% N

EXAMPLE 233N-[2-[4-(1-Ethoxycarbonyl-6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-ethyl]phthalimidemaleate

A mixture ofN-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide (1.8g, 4.6 mmol) and ethyl chloroformate (5.7 g, 52.3 mmol) was heated on astream bath for 10 minutes. The reaction was cooled and an additional2.3 g (20.9 mmol) ethyl chloroformate was added. The reaction wasreturned to the steam bath for 10 minutes longer and then cooled. Theresultant solid was triturated with anhydrous Et₂ O and collected toyield 2.0 g. The solid was suspended in H₂ O (100 ml) and NaHCO₃ wasadded to make the pH≈8. The aqueous mixture was extracted with CH₂ Cl₂and the CH₂ Cl₂ extract was washed with H₂ O, dried with Na₂ SO₄ andconcentrated to afford 2.0 g of a yellow oil that crystallized readily.The product was flashed over 80 g silica gel using 2% Et₂ NH-EtOAc aseluent to afford 1.10 g (2.36 mmol) of an off-white solid. The compoundwas dissolved in hot absolute ethanol (55 ml) and maleic acid (0.28 g,2.36 mmol) was added. The solution was refluxed gently for 10 minutesand then cooled. Most of the ethanol was removed in vacuo and theresultant white suspension was diluted with anhydrous Et₂ O (50 ml). Thesolid that was produced was collected to yield 1.35 g. Recrystallizationfrom CH₃ CN gave 1.15 g of the maleate salt as a white powder, m.p.214-216° C.

ANALYSIS: Calculated for C₂₄ H₂₄ FN₅ O₄.C₄ H₄ O₄ : 57.83% C 4.85% H12.04% N; Found: 57.87% C 4.96% H 11.98% N

EXAMPLE 2343-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-methyl-3H-quinazolin-4-one

A stirred mixture of 3-(4-piperidinyl)-6-fluorobenzisoxazole (4 g, 18.2mmol), K₂ CO₃ (3.76 g, 27.2 mmol) and3-(2-chloroethyl)-2-methyl-3H-4-quinazolinone (6.0 g, 27 mmol) inacetonitrile (300 ml) was heated at reflux for 16 hours. The reactionwas complete as judged by TLC. The solids were filtered and the solventwas evaporated. The residue was purified over a flash chromatographycolumn (SiO₂, 75 gm, eluted with dichloromethane and MeOH indichloromethane). The pure product thus obtained weighed 6.5 gm.Recrystallization from ethanol yielded white crystals, 3.94 gm (53%),m.p. 164-165° C. This material appeared pure by TLC over silica gelplates.

ANALYSIS: Calculated for C₂₃ H₂₃ FN₄ O₂ : 67.97% C 5.70% H 13.78% N;Found: 67.66% C 5.66% H 13.60% N

EXAMPLE 2354-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-[3-(2,3-dihydro-1H-isoindol-2-yl)propyl]piperidinedifumarate

A stirred mixture of3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl amine (3.46g, 12.5 mmol), K₂ CO₃ (4 g, 29 mmol) and α,α-dibromo-o-xylene (3.3 g,12.5 mmol) in acetonitrile (300 ml) was heated at reflux for 3.5 hours.The mixture was cooled and the insolubles were filtered. The dark redsolution was concentrated down to a dark oil. This oil was purified byflash chromatography over a silica gel column (SiO₂, 45 g; eluted withdichlorometliane and MeOH in dichloromethane). The product thus obtainedweighed 1.95 g as an oil. This oil was dissolved in ethanol and wastreated with a solution of fumaric acid (600 mg) in ethanol. Theresulting crystals were collected as an off white solid and weighed 1.44gm, m.p. 206-209° C.

ANALYSIS: Calculated for C₂₃ H₂₆ FN₃ O.2C₄ H₄ O₄ : 60.88% C 5.60% H6.87% N; Found: 60.47% C 5.81% H 6.84% N

EXAMPLE 2364-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-[2-(2,3-dihydro-1H-isoindol-2-yl)ethyl]-piperidinedihydrochloride

A mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.67 g,10.1 mmol), α,α-dibromo-o-xylene (2.76 g, 10.4 mmol) and K₂ CO₃ (3.2 g,23 mmol) in acetonitrile (300 ml) was heated at reflux for 1 hour. Themixture turned pinkish and reaction was complete. The mixture wascooled, then filtered. The solution was concentrated down to a foam.Extraction with ether yielded 1.13 g of off-white solids. This materialwas dissolved into methanol with another batch (1.15 g), prepared in asimilar way, and was treated with ethereal HCl˜ether (15 ml, 1M). Thecrystals which formed weighed 2.35 g, with m.p.=259-262° C.

ANALYSIS: Calculated for C₂₂ H₂₄ FN₃ O₂.2HCl: 60.28% C 5.98% H 9.59% N;Found: 59.98% C 5.83% H 9.48% N

EXAMPLE 2374-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-[2-(5-fluoro-2,3-dihydro-1H-isoindol-2-yl)ethyl]piperidinedifumarate

To a solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-4-fluorophthalimide(4.5 g, 10.9 mmol) in tetrahydrofuran (120 ml) was charged with asolution of lithium aluminum hydride (35 ml, 35 mmol, 1M in ether)dropwise under N₂ at room temperature. The mixture was stirred at roomtemperature for 24 hours. The excess of hydride was quenched carefullywith ice chips and 5 ml of 20% NaOH. The mixture was stirred for 1 hour,diluted with EtOA (200 ml) then filtered. The organic solution wasconcentrated to dryness. The residue was purified by flashchromatography over a silica gel column (SiO₂, 70 gm; eluted with 1% CH₃OH: 99% dichloromethane). The product thus obtained (weighed ˜3.0 g) wasdissolved into ethanol and treated with a solution of fumaric acid (918mg) in ethanol. The crystals formed were collected to yield 2.25 g ofwhite crystals, m.p. 228-229° C.

ANALYSIS:

Calculated for C₂₂ H₂₃ F₂ N₃ O.2C₄ H₄ O₄ : 58.53% C 5.08% H 6.83% N;Found: 58.48% C 4.98% H 6.78% N

EXAMPLE 2384-(6-Fluoro-1,2-benzisoxazol-3yl)-1-[2-(2,3-dihydro-1H-isoindol-2-yl)propyl]piperidinefumarate

A stirred mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propylamine (2.92 g,10.5 mmol), α-α-dibromo-o-xylene (3.0 g, 11.03 mmol) and K₂ CO₃ (3.5 g,25.3 mmol) in aceotnitrile (150 ml) was heated at reflux for 6 hours.The insolubles were filtered off. The solvent was removed on a rotaryevaporator. The residue was purified twice by flash chromatography overa silica gel column (40 g and 45 g of silica gel). The product afterpurification weighed 1.15 g. This oil was treated with a solution offumaric acid (490 mg) in ethanol. The off white crystals were collectedto yield 680 mg, m.p. 164-165° C.

ANALYSIS: Calculated for C₂₃ H₂₆ FN₃ O.C₄ H₄ O₄ : 65.44% C 6.10% H 8.48%N; Found: 64.83% C 6.01% H 8.08% N

EXAMPLE 239N-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propyl]-2,3-dihydro-1H-isoindoledihydrochloride

To a stirred mixture of1-(3-amino-2-hydroxypropyl-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine(2.24 g, 7.6 mmol), K₂ CO₃ (1.61 g, 11.7 mmol) in acetonitrile (100 ml)was added α,α-dibromo-o-xylene (1.54 g, 6.1 mmol). The mixture washeated at reflux for 4 hours then cooled. The insolubles were filtered.The dark red solution was concentrated down. The residue was purified byflash chromatography over s silica gel column (SiO₂, 30 g; eluted with1% CH₃ OH in dichloromethane). The product so obtained weighed 940 mg asan oil. This oil was dissolved in ethanol and was treated with asolution of HCl in ethanol (188 mg of AcCl in ethanol). The dark solidswere collected and recrystallized again in ethanol to yield off-whitecrystals (1.01 g), m.p. 240-243° C.

ANALYSIS: Calculated for C₂₃ H₂₆ FN₃ O₂.2HCl: 58.98% C 6.03% H 8.97% N;Found: 58.72% C 6.16% H 8.94% N

EXAMPLE 240N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-5-(triisopropylsilyl)oxy-1H-isoindoledifumarate

A mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (1.52 g,5.73 mmol), 1,2-dibromo-4-(triisopropylsilyl)oxy-xylene (2.4 g, 5.7mmol) and K₂ CO₃ (1.8 g, 13 mmol) in acetonitrile (300 ml) was stirredovernight (18 hours) at room temperature. The mixture was filtered andthe solvent was stripped. The residue was purified by flashchromatography over a silica gel column (7 gm of SiO₂ ; eluted with 1-3%CH₃ OH in dichloromethane. The product thus purified (weight: 900 mg)was converted to the fumarate salt by treatment with fumaric acid (194mg) in hot ethanol. The crystals were collected and weighed 590 mg, m.p.208-210° C.

ANALYSIS: Calculated for C₃₁ H₄₄ FN₃ O₂ Si.2C₄ H₄ O₄ : 60.84% C 6.81% H5.46% N; Found: 60.41% C 6.87% H 5.35% N

EXAMPLE 241N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-2,3-dihydro-5-hydroxy-1H-isoindolefumarate hydrate

To a stirred solution ofN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-5-(triisopropylsilyl)oxy-1H-isoindole(11.5 g, 21.5 mmol) in tetrahydrofuran (50 ml) was added a solution oftetrabutyl ammonium fluoride (1M in tetrahydrofuran, 24 ml, 24 mmol) inportions at room temperature. The mixture was stirred for 2 hours, thendiluted with methylene chloride (200 ml). The organics was washed withH₂ O and brine, dried with anhydrous MgSO₄. The solvents were removedand the residue was purified by flash chromatography over a silica gelcolumn (90 g of SiO₂ ; eluted with 1-4% of CH₃ OH in methylenechloride). The desired fractions were combined and concentrated to give1.5 g of free base. This solid was recrystallized from ethanol to yield570 mg of off white crystals. The crystals were converted to fumaratesalt in hot ethanol and water to give pinkish crystals, 560 mg, m.p.191-193° C.

ANALYSIS: Calculated for C₂₂ H₂₄ FN₃ O₂.C₄ H₄ O₄.H₂ O: 60.57% C 5.87% H8.15% N; Found: 60.20% C 5.73% H 8.04% N

EXAMPLE 2424-(6-Fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-1H-isoindol-2-yl)ethyl]-piperidinedimaleate

To a solution ofN-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimidehydrochloride (Example 183) (3.1 g, 7.91 mmol) in THF (100 ml) was addedlithium aluminum hydride (16.6 ml of a 1.0M solution in THF, 16.6 mmol)at room temperature, under nitrogen. The reaction mixture was warmed toreflux for 6.5 hours and cooled to room temperature. The reaction wasquenched with water (1.5 ml, dropwise) and the precipitated salts wereremoved via filtration. The solids were washed with DCM and the combinedfiltrates concentrated to give 2.5 g of the crude product as a solid.The dimaleate salt was prepared in methanol using 3.5 g (>4.0 e.q.) ofmaleic acid. The light green precipitate was collected via filtrationand washed with methanol. Recrystallization from methanol gave 2.1 g ofthe desired product as an off-white solid, m.p. 196-199° C.

ANALYSIS: Calculated for C₂₂ H₂₅ FN₄.2C₄ H₄ O₄ : 60.40% C 5.58% H 9.39%N; Found: 60.33% C 5.42% H 9.42% N

EXAMPLE 2432-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(2,3dihydro-1H-isoindol-2-yl)-ethanone

(A) 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetamide

The mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (6.77 g,30.7 mmol), K₂ CO₃ (5 g, 36.2 mmol) and 2-bromoacetamide (4.46 g, 32.3mmol) in acetonitrile (250 ml) was heated to reflux for 4 hours. Theinsolubles were filtered and rinsed with dichloromethane (DCM). Thesolvents were removed. The residual solid was dissolved in DCM and uponconcentration of this solution, 2.3 g of product crystallized out andwas collected when the volume was reduced to about 50 ml. The rest ofthe product in DCM was purified by flash chromatography over a silicagel column (80 gm, SiO₂ ; eluted with DCM and 1% CH₃ OH in DCM). Thetotal product (4.2 g) thus purified was recrystallized from ethanol toyield 2.82 g of white crystals, m.p. 170-172° C. dec.

ANALYSIS: Calculated for C₁₄ H₁₆ FN₃ O₂ : 60.64% C 5.82% H 15.15% N;Found: 60.66% C 5.87% H 15.10% N

(B)2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(2,3-dihydro-1H-isoindol-2-yl)-ethanone

To a mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetamide (2.56 g,9.2 mmol) in DMF (40 ml) was chipped in sodium hydride (770 mg, 60% inoil, 20.1 mmol) at room temperature under N₂. The mixture was heated to65° C. for 3 hours. α,α-dibromoxylene (2.43 g, 9.2 mmol) was added andthe resulting mixture was heated at 70° C. for 4 hours, then leftstanding overnight for 16 hours. The DMF mixture was poured into H₂ O(400 ml) and the organics were extracted into ethyl acetate (250 ml).The ethyl acetate solution was washed with brine and dried over MgSO₄.The solvent was removed and the residue was purified by flashchromatography over a silica gel column (SiO₂, 45 gm; eluted with 1% CH₃OH: 99% DCM). The product thus purified as a white solid weighed 1.73 g.Recrystallization from a small amount of ethanol yielded white crystals:1.65 g, m.p. 184-185° C.

ANALYSIS: Calculated for C₂₂ H₂₂ FN₃ O₂ : 69.64% C 5.84% H 11.07% N;Found: 69.48% C 5.67% H 11.05% N

EXAMPLE 2442-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(2,3-dihydro-1H-isoindol-2-yl)ethanonefumarate

Free base (1 g, Example 243B) of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(2,3-dihydro-1H-isoindol-2-yl)ethanonedissolved in hot ethanol (˜10 ml) was treated with a solution of fumaricacid (306 mg) in hot ethanol. The mixture was cooled and the productcollected, 1.2 gm, m.p. 223-225° C.

ANALYSIS: Calculated for C₂₂ H₂₂ FN₃ O₂.C₄ H₄ O₄ : 63.02% C 5.29% H8.48% N; Found: 62.86% C 5.03% H 8.39% N

EXAMPLE 2454-(6-Fluoro-1H-indazol-3-yl)-1-[2-(5-fluoro-2,3-dihydro-1H-isoindol-2-yl)ethyl]piperidinedimaleate

To a solution consisting of2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethylamine (6.1 g, 23.2mmol) in DMF (230 ml) was added 4-fluorophthalic anhydride (4.2 g, 25.5mmol) at room temperature, under nitrogen. The reaction mixture waswarmed to 80° C. for 2.5 hours at which time it was allowed to cool toroom temperature. The DMF was removed under reduced pressure (<0.5 mmHg,55° C.) to give a brown oil which was dissolved into DCM/MeOH.Purification via flash column chromatography (silica gel, 2% MeOH/DCM)afforded 3.6 g of4-fluoro-N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimide.To a solution of the latter compound (3.6 g 8.8 mmol) in anhydrous THF(100 ml) was added LAH (18.4 ml of a 1.0M solution in THF, 18.4 mmol) atroom temperature, under nitrogen. The reaction mixture was warmed toreflux for 4 hours. Upon cooling to room temperature, the reaction wasquenched with water (1.5 ml, dropwise). The precipitated salts wereremoved via filtration and washed with DCM. The combined filtrates wereconcentrated to give a solid which was purified via flash columnchromatography (silica gel, 0-8% MeOH/DCM). The product containingfractions were concentrated to give 2.4 g product as an off-white solid.The dimaleate salt was prepared in methanol using 2.4 eq. of maleicacid. The white precipitate was collected via filtration and washed withmethanol, m.p. 186-188° C.

ANALYSIS: Calculated for C₂₂ H₂₄ F₂ N₄. 2C₄ H₄ O₄ : 58.63% C 5.25% H9.12% N; Found: 58.45% C 5.29% H 9.07% N

EXAMPLE 2464-(1H-Indazol-3-yl)-1-[2-(2,3-dihydro-5-fluoro-1H-isoindol-2-yl)ethyl]-piperazinedimaleate

To a suspension consisting of4-fluoro-2-[2-[4-(1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide (4.8g, 12.1 mmol) in THF (120 ml) was added LAH (dropwise, 25.5 ml of a 1.0Msolution in THF, 25.5 mmol) at room temperature, under nitrogen. Thereaction mixture was warmed to reflux for 4 hours during which time itbecame homogeneous. Upon cooling to room temperature, the reaction wascarefully quenched with water (11.5 ml) and the precipitated salts wereremoved via filtration and washed with DCM. The combined filtrates wereconcentrated to give the crude product. This material was dissolved intoDCM/MeOH (minimal) and purified via preparative HPLC (single column ofsilica gel, 5% MeOH/DCM, 4 L, then increased to 10% MeOH/DCM, 3 L) togive 2.9 g of the desired product. The dimaleate salt was prepared inmethanol (200 ml) using maleic acid (2.2 eq., 2.0 g, 17.5 mmol). Theresulting salt was collected via filtration and washed with methanol togive an off-white solid, m.p. 182-184° C.

ANALYSIS: Calculated for C₂₁ H₂₄ FN₅.2C₄ H₄ O₄ : 58.29% C 5.40% H 11.72%N; Found: 57.96% C 5.39% H 11.65% N

EXAMPLE 2474-(6-Fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-4-methyl-1H-isoindol-2-yl)ethyl]piperazinedifumarate

To a stirred solution of2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-3-methylphthalimide(5.4 g, 13.3 mmol) in THF (200 ml) under N₂ was added, dropwise, LAH(30.0 ml of a 1.0M LAH/THF solution). After complete addition, thereaction was stirred at reflux for 4.5 hours. The reaction was cooled inan ice bath and H₂ O (2 ml) was carefully added followed by 1.0M NaOH (3ml). The mixture was filtered and the filtrate was concentrated to yield5.0 g of a brown oil. Trituration of the oil with Et₂ O produced a whitesolid that was isolated by filtration to give 2.1 g of a white solid.The compound was purified via preparative HPLC (Water's Associates PrepLC/500 using 2 silica gel columns and eluting initially with 10%MeOH-CH₂ Cl₂ changing to 15% MeOH-CH₂ Cl₂). Concentration of appropriatefractions yielded 1.5 g (4.0 mmol) of a beige solid. The compound wasdissolved in EtOAc (125 ml) and MeOH (4 ml) and the solution was warmedand filtered. The filtrate was stirred near reflux and a solution offumaric acid (0.92 g, 8.0 mmol) in hot MeOH-EtOAc (1:1, 8 ml) was added.The mixture was allowed to cool and the resultant product was collectedto give 2.1 g of an off-white solid, m.p. 212-215° C.

ANALYSIS: Calculated for C₂₂ H₂₆ FN₅.2C₄ H₄ O₄ : 58.91% C 5.60% H 11.45%N; Found: 58.88% C 5.66% H 11.62% N

EXAMPLE 2484-(6-Fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-5-methyl-1H-isoindol-2-yl)-ethyl]piperazinedifumarate

To a stirred solution of2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-4-methylphthalimide(5.46, 13.3 mmol) in THF (200 ml) under N₂ was added, dropwise, LAH(30.0 ml of a 1.0M LAH/THF solution). After complete addition, thereaction was stirred at reflux for 4.5 hours. The reaction mixture wascooled in an ice bath and H₂ O (2 ml) was carefully added followed by1.0M NaOH (3 ml). The mixture was filtered and the filtrate wasconcentrated to yield 4.7 g of a brown solid. The compound wastriturated with Et₂ O and filtered to give 2.4 g of a white solid. Thecompound was purified by preparative HPLC (Water's Associates Prep 500using 2 silica gel columns and eluting initially with 10% MeOH-CH₂ Cl₂switching to 15% MeOH-CH₂ Cl₂). Concentration of appropriate fractionsgave 1.7 g (4.5 mmol) of a beige solid. The solid was dissolved in EtOAc(130 ml) and MeOH (4 ml) and filtered. The filtrate was stirred nearreflux and was treated with a solution of fumaric acid (1.04 g, 9.0mmol) dissolved in hot MeOH (6 ml) and EtOAc (6 ml). The mixture wascooled to ambient temperature and the salt was isolated by filtration toprovide 2.4 g of an off-white solid, m.p. 212-215° C.

ANALYSIS: Calculated for C₂₂ H₂₆ FN₅.2C₄ H₄ O₄ : 58.91% C 5.60% H 11.45%N; Found: 58.63% C 5.35% H 11.41% N

EXAMPLE 2494-(6-Fluoro-1H-indazol-3-yl)-1-[2-(5-fluoro-2,3-dihydro-1H-isoindol-2-yl)-ethyl]piperazinedimaleate

To a stirred solution of2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]-ethyl]-4-fluorophthalimide(2.9 g, 7.1 mmol) in THF (100 ml) under N₂ was added, dropwise, LAH(16.0 ml of a 1.0M LAH/THF solution) over 30 minutes. The reaction wasstirred at ambient temperature for 1 hour, reflux for 3.5 hours and thenat ambient for 18 hours. The reaction was cooled in an ice bath and H₂ O(2 ml) was carefully added followed by 1.0M NaOH (2 ml). The mixture wasfiltered and the filter cake was rinsed with 10% MeOH-EtOAc. Thefiltrate was concentrated to yield 2.5 g of a beige solid. The compoundwas purified by preparative HPLC (Waters Associates Prep 500 using 2silica gel columns and eluting initially with 8% MeOH-CH₂ Cl₂ increasingthe polarity to 12% MeOH-CH₂ Cl₂) to yield 1.7 g (4.3 mmol) of a greysolid. The compound was dissolved in warm EtOAc (75 ml) and MeOH (7 ml)and filtered. The filtrate was warmed and stirred and maleic acid (1.0g, 8.6 mmol) was added. The reaction was stirred at gentle reflux for 15minutes and then at ambient temperature for 45 minutes. Anhydrous Et₂ O(100 ml) was added and the solid was collected to give 2.5 g.Recrystallization from CH₃ CN provided 1.7 g of the dimaleate salt as alight grey solid, m.p. 196-199° C.

ANALYSIS: Calculated for C₂₁ H₂₃ F₂ N₅.2C₄ H₄ O₄ : 56.58% C 5.08% H11.38% N; Found 56.38% C 5.01% H 11.38% N

EXAMPLE 2504-(1H-Indazol-3-yl)-1-[2-(2,3-dihydro-1H-isoindol-2-yl)ethyl]piperazinedimaleate

A suspension of 4-(1H-indazol-3-yl)piperazine (1.6 g, 7.9 mmol),N-(2-bromoethyl)phthalimide (2.1 g, 7.9 mmol), and sodium bicarbonate(0.7 g, 8.3 mmol) in acetonitrile (160 ml) was warmed to reflux for 24hours. Upon cooling to room temperature, the reaction mixture wasfiltered through a pad of celite and the solids were washed with DCM.The combined filtrates were concentrated to give theN-[2-[4-(1H-indazol-3-yl)-1-piperazinyl]ethyl]phthalimide which was usedwithout further purification.

To a suspension consisting ofN-[2-[4-(1H-indazol-3-yl)-1-piperazinyl]ethyl]-phthalimide 2.9 g, 7.9mmol) in THF (100 ml) was added LAH (dropwise, 19.0 ml of a 1.0Msolution in THF, 19.0 mmol) at room temperature, under nitrogen. Thereaction mixture was warmed to reflux for 4 hours during which time itbecame homogeneous. Upon cooling to room temperature, the reaction wascarefully quenched with water (1.5 ml) and the precipitated salts wereremoved via filtration and washed with DCM. The combined filtrates wereconcentrated to give the crude product as an oil. Purification via flashcolumn chromatography (silica gel, 5% MeOH/DCM) afforded 0.77 g of thedesired product. The dimaleate salt was prepared in methanol usingmaleic acid (2.1 eq., 0.54 g). The resulting salt was collected viafiltration and washed with methanol to give a greenish solid, m.p.178-183° C.

ANALYSIS: Calculated for C₂₁ H₂₅ N₅.2C₄ H₄ O₄ : 60.10% C 5.74% H 12.08%N; Found: 59.82% C 5.65% H 12.10% N

EXAMPLE 2514-(6-Fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-1H-isoindol-2-yl)-ethyl]piperazinedimaleate

To a stirred solution ofN-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-phthalimide (5.5g, 14.0 mmol) in THF (125 ml) under N₂ at ambient temperature was added,dropwise, LAH (33.0 ml of a 1.0M LAH/THF solution) over 30 minutes.After complete addition the reaction was stirred at ambient temperaturefor 45 minutes, and then at reflux for 4.5 hours. After stirring atambient temperature for 64 hours, the reaction was cooled in an ice bathand H₂ O (5.0 ml) was carefully added followed by 1M NaOH (2 ml). Thereaction was filtered and the oily filter cake was rinsed with THF and10% MeOH-EtOAc. The combined organic filtrate was concentrated to afford5.5 g of a sticky white substance. This was combined with an additionalsample (7.5 g total) and purification via preparative HPLC (Water'sAssociates Prep LC/500 using 2 silica gel columns and 10% MeOH-CH₂ Cl₂as eluent) provided 6.0 g (16.4 mmol) of a beige solid. The product wasdissolved in warm EtOAc (150 ml) and treated with Darco-G60 for 20minutes. The decolorizing carbon was removed by filtration through a bedof celite and the warm filtrate was treated with a solution of maleicacid (3.8 g, 32.8 mmol) in hot EtOH (17 ml). A white solid precipitatedand the mixture was stirred 1.5 hours at ambient temperature. Thecompound was isolated by filtration to afford 8.9 g of a light greysolid. Recrystallization from MeOH gave 5.2 g of the dimaleate salt,m.p. 205-207° C.

ANALYSIS: Calculated for C₂₁ H₂₄ FN₅.2C₄ H₄ O₄ : 58.29% C 5.40% H 11.72%N; Found: 58.27% C 5.31% H 11.69% N

EXAMPLE 2526-Fluoro-3-[4-[2-(2,3-dihydro-1H-isoindol-2-yl)ethyl]-1-piperazinyl]-N-phenyl-1H-indazole-1-carboxamidedimaleate

To a stirred suspension of NaH (0.40 g of 60% oil dispersion; 10.0 mmol)in DMF (10 ml) under N₂ and cooled to -3° C., was added, dropwise, asolution of4-(6-fluoro-1H-indazol-3-yl)-1-[2,3-dihydro-1H-isoindol-2-yl)ethyl]piperazine(3.3 g, 9.0 mmol) in DMF (45 ml) over 60 minutes, maintaining thetemperature below 0° C. The mixture was stirred for 60 minutes at 0° C.and then a solution of phenyl isocyanate (1.2 g, 10.0 mmol) in DMF (5ml) was added dropwise at -2° C. After complete addition the reactionwas stirred at ambient temperature for 20 hours. The reaction was pouredinto H₂ O, and the aqueous mixture was extracted with ethyl acetate. Theethyl acetate extract was washed with H₂ O, washed with brine, driedwith MgSO₄, and concentrated to afford 5.6 g of a dark oil. The oil waspurified by preparative HPLC (Waters Associates Prep 500 using 2 silicagel columns and 4% MeOH-CH₂ Cl₂ as eluent) to yield 2.9 g of a dark oil.A 2.7 g (5.6 mmol) sample was dissolved in warm EtOAc (100 ml) and MeOH(5 ml) and the particulate matter was filtered away. The filtrate waswarmed and stirred and a solution of maleic acid (1.3 g, 11.2 mmol) inhot MeOH (5 ml) was added. The reaction was refluxed mildly for 15minutes and then was stirred at ambient temperature for 2 hours. Theresultant suspension was diluted with petroleum ether (150 ml) and thedark solid collected to yield 3.2 g. The compound was recrystallizedfrom CH₃ CN (utilizing Darco G-60 decolorizing carbon) to afford 1.6 gof a grey solid, m.p. 189-191° C.

ANALYSIS:

Calculated for C₂₈ H₂₉ FN₆ O.2C₄ H₄ O₄ : 60.33% C 5.20% H 11.73% N;Found: 60.36% C 4.86% H 11.85% N

EXAMPLE 2534-(1-Decanoyl-6-fluoro-1H-indazol-3-yl)-1-[2-(2,3-dihydro-1H-isoindol-2-yl)ethyl]piperazinedimaleate

To a stirred suspension of NaH (0.40 g of 60% oil dispersion, 10.0 mmol)in DMF (10 ml) under N₂ and cooled to -3° C. was added, dropwise, asolution of4-(6-fluoro-1H-indazol-3-yl)-1H-[2-(2,3-dihydro-1H-isoindol-2-yl)ethyl]piperazine(3.3 g, 9.0 mmol) in DMF (45 ml) over 65 minutes so that the temperaturewas maintained below 0° C. The reaction was stirred for 1 hour and wascooled to -2° C. A solution of decanoyl chloride (1.9 g, 10.0 mmol) inDMF (5 ml) was added dropwise over 10 minutes. After complete additionthe reaction was stirred at ambient temperature for 20 hours. Thereaction was poured into H₂ O (75 ml) and the aqueous mixture wasextracted with EtOAc. The EtOAc extract was washed with H₂ O, washedwith brine, dried with MgSO₄ and concentrated to afford 5.1 g of a darkoil. The oil was purified by preparative HPLC (Water's Prep 2000utilizing 1 silica gel column and 4% MeOH-CH₂ Cl₂ as eluent) to yield3.1 g (66%) of a dark oil. The oil (2.75 g, 5.3 mmol) was dissolved inwarm EtOAc (100 ml) was treated with maleic acid (1.26 g, 10.9 mmol).After warming for 30 minutes the grey suspension was stirred at ambienttemperature for 60 minutes. The reaction was diluted with anhydrous Et₂O (30 ml) and petroleum ether (200 ml) and the resultant dark grey solidwas collected to yield 3.77 g. The salt was recrystallized from CH₃ CN(using Darco G-60) to yield 2.6 g of a light grey solid, m.p. 191-194°C.

ANALYSIS: Calculated for C₃₁ H₄₂ FN₅ O.2C₄ H₄ O₄ : 62.30% C 6.70% H9.31% N; Found: 62.34% C 6.74% H 9.23% N

EXAMPLE 2544-(6-Fluoro-1H-indazol-3-yl)-1-[3-(2,3dihydro-1H-isoindol-2-yl)propyl]-piperazinedimaleate

To a stirred solution of2-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]propyl]phthalimide (5.3g, 13.0 mmol) in THF (200 ml) under N₂ was added, dropwise, LAH (27.0 mlof a 1.0M LAH/THF solution). After complete addition, the reaction wasstirred at reflux for 4.5 hours. The reaction was cooled in an ice bathand H₂ O (2 ml) was carefully added, followed by 1.0M NaOH (3 ml). Themixture was filtered and the filtrate was concentrated to afford 4.8 gof a white solid. The compound was purified by preparative HPLC (Water'sAssociates Prep 500, utilizing 2 silica gel columns and 5% Et₂ NH-EtOAcas eluent) to give 3.0 g of a beige solid. Recrystallization from EtOAcprovided 1.1 g (2.9 mmol) of an off white solid. The compound wasdissolved in hot EtOAc (200 ml) and MeOH (10 ml) and maleic acid (0.68g, 5.8 mmol) was added. The reaction was warmed for 15 minutes and afterstirring at ambient temperature for 30 minutes and standing at about 4°C. for 1.5 hours, the dimaleate salt was collected to yield 1.7 g of anoff-white solid, m.p. 183-186° C.

ANALYSIS: Calculated for C₂₂ H₂₆ FN₅.2C₄ H₄ O₄ : 58.91% C 5.60% H 11.45%N; Found: 58.92% C 5.47% H 11.53% N

EXAMPLE 2552-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(2,3-dihydroindol-1-yl)ethanonefumarate

A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (10 g,45.4 mmol), K₂ CO₃ (7.2 g, 52.5 mmol) and N-(2-bromoacetyl)indoline (12g, 50 mmol) in acetonitrile (300 ml) was heated at reflux for 4 hours.The mixture was cooled and filtered. The solution was concentrated downuntil solid appeared. The crystals were collected: weight 12.68 g. Themother liquor was concentrated to dryness. The residues were purifiedfurther by flash chromatography to yield an additional 1.35 g. Totalyield was 14.03 g. A 2 g sample was dissolved in ethanol/methylenechloride and was treated with a solution of fumaric acid (612 mg) inethanol to yield 2.58 g, m.p. 226-227° C.

ANALYSIS: Calculated for C₂₂ H22FN₃ O₂.C₄ H₄ O₄ : 63.02% C 5.29% H 8.48%N; Found: 62.79% C 5.30% H 8.40% N

EXAMPLE 2561-(1,2,3,4-Tetrahydro-1H-isoquinolin-2-yl)-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethanonehydrochloride ethanolate

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.33 g, 19.7mmol), K₂ CO₃ (3.45 g, 25 mmol, 1.25 eq) and2-bromoacetyl-1,2,3,4-tetrahydroisoquinoline (5 g, 20 mmol) inacetonitrile (200 ml) was heated at reflux for 2 hours. The reaction wascooled and the insolubles were filtered. The solvent was removed and thecrude oil was purified by flash chromatography over a silica gel column(90 g of SiO₂ ; eluted with DCM and 1% CH₃ OH in DCM). The oil thuspurified weighed 6.41 g. A 3 g sample was dissolved into ethanol (20 ml)and was treated with 1M-HCl-ether solution (10 ml). The crystals werecollected and recrystallized twice from ethanol to yield 2.43 g of whitecrystals as the hydrochloride ethanolate, m.p. 206-208° C.

ANALYSIS: Calculated for C₂₃ H₂₄ FNO₂.HCl.C.₂ H₆ O: 63.08% C 6.56% H8.83% N; Found: 63.24% C 6.62% H 8.89% N

EXAMPLE 257N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-1,2,3,4-tetrahydroisoquinolinedifumarate

To a solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(1,2,3,4-tetrahydro-1H-isoquinolin-2-yl)ethanone(2.36 g, 6 mmol) in THF (40 ml) was charged lithium aluminum hydride (15ml, 1M in ether) dropwise under N₂ at room temperature. The mixture wasstirred for 3 hours at room temperature. At the end, the excess ofhydride was quenched with ice chips and 2 ml of 20% NaOH. The mixturewas diluted with EtOAc and filtered. The solvents were removed todryness. The residue was purified by flash chromatography over a silicagel column (SiO₂, 18 g; eluted with 1% CH₃ OH in DCM). The product thusobtained weighed 1.62 g. This material was dissolved into hot ethanoland was treated with a solution of fumaric acid (490 mg) in ethanol. Themixture was cooled and the crystals were collected to yield 1.15 g, m.p.218-220° C.

ANALYSIS: Calculated for C₂₃ H₂₆ FN₃ O.2C₄ H₄ O₄ : 60.88% C 5.60% H6.87% N; Found: 61.00% C 5.50% H 6.64% N

EXAMPLE 2582-(1,2,3,4-Tetrahydro-1H-isoquinolin-2-yl)-1-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethanonefumarate

(A) 1-(2-Chloroacetyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine

A solution of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.4 g, 20mmol), triethylamine (2.1 g, 21 mmol) in chloroform (50 ml) was added toa solution of chloroacetyl chloride (2.5 g, 22 mmol) in chloroform (100ml) dropwise at room temperature. The mixture was stirred for 2 hours.The solution was diluted with dichloromethane (DCM, 100 ml) and thenwashed with H₂ O and brine. The solvent was removed and the oily productwas purified by flash chromatography (SiO₂, 50 g; eluted with DCM and 1%CH₃ OH in DCM). The pure product was obtained as an oil, 4.2 g.Crystallization from ethanol yielded 2.2 g of white crystals, m.p.101-102° C.

ANALYSIS: Calculated for C₁₄ H₁₄ ClFN₂ O₂ : 56.67% C 4.76% H 9.44% N;Found: 56.70% C 4.75% H 9.46% N

(B)2-(1,2,3,4-Tetrahydro-1H-isoquinolin-2-yl)-1-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethanonefumarate

A mixture of4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl-2-chloroacetamide (3.0g, 10.8 mmol), K₂ CO₃ (1.5 gm, 10.8 mmol) and1,2,3,4-tetrahydroisoquinoline (1.4 g, 10.5 mmol) in acetonitrile (90ml) was heated at reflux for 4 hours. The reaction was cooled andfiltered. The solvent was removed, and the residue was purified by flashchromatography over a silica gel column (50 g of SiO₂ ; eluted with DCMand 1% CH₃ OH in DCM). The light yellow oil (3.28 g) thus obtained wasdissolved in ethanol and treated with a solution of fumaric acid (968mg) in ethanol. The solid crystals were collected and recrystallizedagain to give 3.18 g of off-white crystals, m.p. 188-189° C.

ANALYSIS: Calculated for C₂₃ H₂₄ FN₃ O₂.C₄ H₄ O₄ : 63.65% C 5.54% H8.25% N; Found: 63.42% C 5.33% H 8.16% N

EXAMPLE 259N-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propyl]-1,2,3,4-tetrahydroisoquinolinedifumarate

A mixture ofN-[3-(2,3-epoxy)propyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine(3.56 g, 12.9 mmol) and 1,2,3,4-tetrahydroisoquinoline (2.06 g, 15.4mmol) in isopropyl alcohol (150 ml) was heated at reflux for 4 hours. Atthe end of the reaction, the solvent was removed. The residual oil waspurified by flash chromatography over a silica gel column (SiO₂, 45 g,eluted with 1% CH₃ OH: 99% methylene chloride). The product thuspurified as a light oil, weighed 4.15 g. The oil was treated with asolution of fumaric acid (1.98 gm, 17 mmol) in ethanol. The whitecrystals so obtained were recrystallized in a large volume of hotethanol (˜150 ml). The recrystallized crystals weighed 2.75 g, m.p.179-181° C.

ANALYSIS: Calculated for C₂₄ H₂₈ FN₃ O₂.2C₄ H₄ O₄ : 59.90% C 5.66% H6.55% N; Found: 60.06% C 5.77% H 6.36% N

EXAMPLE 2606,7-Dimethoxy-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propyl]-1,2,3,4-tetrahydroisoquinoline

A stirred mixture of1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.2 g,11.6 mmol), K₂ CO₃ (2 gm, 1.25 eq) and6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.3 g, 1.25eq) in isopropyl alcohol (200 ml) was heated at reflux for 6 hours. Themixture was cooled and filtered. The solvent was removed to about 50 mland the solution was allowed to stand overnight. Crystals (0.6 g) formedand were collected. The mother liquor was concentrated to a white solid.Recrystallization twice from ethanol yielded the product (1.95 g, m.p.153-154° C.

ANALYSIS: Calculated for C₂₆ H₃₂ FN₃ O₄ : 66.51% C 6.87% H 8.95% N;Found: 66.51% C 7.05% H 8.83% N

EXAMPLE 261N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]-1,2,3,4-tetrahydroisoquinolinedimaleate

To a solution of 4-(6-fluoro-1H-indazol-3-yl)piperidine (4.8 g, 18.9mmol) in CH₃ CN (200 ml) was added2-bromo-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethanone (4.8 g, 18.9mmol) and sodium bicarbonate (1.9 g, 22.7 mmol) at room temperature. Thereaction mixture was warmed to reflux (4 hours), cooled to roomtemperature and filtered through a pad of celite. The solids were washedwith DCM and the combined filtrates were concentrated. The remainingresidue was purified via preparative HPLC (silica gel, 5-10% MeOH/DCM)to give 4.1 g of1-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethanonewhich was used without further purification. To a suspension of thelatter (3.7 g, 9.4 mmol) in THF (100 ml) was added (dropwise) lithiumaluminum hydride (11.3 ml of 1.0M solution in THF, 11.3 mmol) at roomtemperature, under nitrogen. The reaction mixture was warmed to reflux(5 hours), cooled to room temperature and carefully quenched with water(10 ml). The precipitated salts were removed via filtration and washedwith 1:1 EtOAc/DCM. The combined filtrates were concentrated and theremaining oil was purified via flash column chromatography (silica gel,10% MeOH/DCM) to give 2.2 g of the product. The dimaleate salt wasprepared in methanol (30 ml) with maleic acid (3.0 eq.), m.p. 185-187°C.

ANALYSIS: Calculated for C₂₃ H₂₇ FN₄.2C₄ H₄ O₄ : 60.98% C 5.78% H 9.18%N; Found: 60.85% C 5.75% H 9.09% N

EXAMPLE 2622-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]-1-(1,2,3,4-tetrahydro-1H-isoquinolin-2-yl)ethanonedifumarate

A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (3.1 g, 14 mmol),2-bromoacetyl-1,2,3,4-tetrahydroisoquinoline (3.6 g, 14 mmol), NaHCO₃(1.4 g, 17 mmol) and CH₃ CN (150 ml) was stirred at reflux under N₂ for6 hours. The cooled reaction was filtered and the filtrate wasconcentrated to yield 6.1 g of an off-white foam. The compound waspurified by preparative HPLC (Water's Associates prep 500 using 2 silicagel columns and 5% MeOH-CH₂ Cl₂ as eluent). Concentration of appropriatefractions gave 4.1 g of an off-white solid. A 0.8 g (2.0 mmol) samplewas dissolved in warm EtOAc (30 ml) and MeOH (4 ml) and filtered. Thefiltrate was heated to reflux and was treated with a solution of fumaricacid (0.47 g, 4.0 mmol) in MeOH/EtOAc (1:1, 8 ml). The mixture wascooled and the resultant white solid was collected to yield 0.88 g. Thiswas combined with another small sample (1.0 g total) andrecrystallization from ethanol provided 0.75 g of a white solid, m.p.235-238° C.

ANALYSIS: Calculated for C₂₂ H₂₄ FN₅ O.2C₄ H₄ O₄ : 57.60% C 5.16% H11.19% N; Found: 57.68% C 5.26% H 11.31% N

EXAMPLE 263N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-1,2,3,4-tetrahydroisoquinolinedifumarate

To a stirred solution of2-[4-(6-fluoro-1H-indazole-3-yl)-1-piperazinyl]-1-(1,2,3,4-tetrahydro-1H-isoquinolin-2-yl)ethanone(3.2 g, 8.1 mmol) in THF (75 ml) under N₂, was added dropwise, LAH (20.0ml of a 1.0M LAH/THF solution). After complete addition, the reactionwas stirred at ambient temperature for 20 hours. The reaction was cooledin an ice bath and cold H₂ O was added followed by 1 ml of 1.0M NaOH.The mixture was filtered and the filter cake was washed with EtOAc. Thefiltrate was concentrated to yield 2.5 g of a white solid. The compoundwas purified by preparatige HPLC (Water's Associates Prep 500, using 1silica gel column and 10% MeOH-CH₂ Cl₂ as eluent) to yield 2.0 g of awhite solid. A 1.8 g (4.7 mmol) sample was stirred as a solution in warmEtOAc (100 ml) and was treated with a solution of fumaric acid (1.1 g,9.5 mmol) in boiling MeOH (12 ml). The reaction was warmed for 15minutes and after stirring at ambient temperature for 1.5 hours theresultant white solid was collected to yield 2.7 g of the difumaratesalt, m.p. 210-213° C.

ANALYSIS: Calculated for C₂₂ H₂₆ FN₅.C₄ H₄ O₄ : 58.91% C 5.60% H 11.45%N; Found: 58.77% C 5.42% C 11.22% N

EXAMPLE 2641-(1,2,3,4-Tetrahydro-1H-quinolin-1-yl)-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethanonefurmarate

A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.7g, 21.4 mmol), K₂ CO₃ (3.6 g, 25.6 mmol) andN-(2-bromoacetyl)-1,2,3,4-tetrahydroquinoline (6 g, 23.6 mmol) inacetonitrile (200 ml) was heated at reflux for 1.5 hours. The mixturewas cooled and the solids were filtered off. The solvent was stripped todryness. The residue was purified by flash chromatography (SiO₂, 100 gm;eluted with methylene chloride (DCM) and 1% CH₃ OH in DCM). The productthus purified weighed 7.75 g. A sample of 1.88 g in ethanol was treatedwith a solution of fumaric acid (550 mg, 1.0 eq) in ethanol to yield thefumaric salt, 2.15 g, m.p. 162-163° C.

ANALYSIS: Calculated for C₂₃ H₂₄ FN₃ O₂.C₄ H₄ O₄ : 63.65% C 5.54% H8.25% N; Found: 63.52% C 5.46% H 8.17% N

EXAMPLE 265N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,2,3,4-tetrahydroquinolinefumarate

To a stirred solution of2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-(1,2,3,4-tetrahydroquinolin-1-yl)ethanone(5.5 g, 14 mmol) in THF (50 ml) was charged with lithium aluminumhydride (17 ml, 17 mmol, 1M in ether) dropwise under N₂ at roomtemperature. The mixture was stirred for 8 hours at room temperature. Atthe end of this period the excess of hydride was quenched with ice chipsand 3 ml of 20% NaOH. The mixture was diluted with EtOAc (150 ml) andstirred for 1 hour. The EtOAc was dried with MgSO₄ and filtered. Thesolvent was removed to dryness. The residue was purified by flashchromatography over a silica gel column (SiO₂, 55 g; eluted with 1-3%CH₃ OH: DCM). The product thus obtained weighed 1.83 g. This materialwas dissolved into hot ethanol and was treated with a solution offumaric acid (700 mg) in ethanol. The crystals were collected andweighed 1.85 g, m.p. 192-193° C.

ANALYSIS: Calculated for C₂₃ H₂₆ FN₃ O.C₄ H₄ O₄ : 65.44% C 6.10% H 8.48%N; Found: 65.20% C 6.19% H 8.32% N

EXAMPLE 266N-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)-2-hydroxy-1-propyl]-1,2,3,4-tetrahydroquinolinehemifumarate

A stirred mixture ofN-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.41g, 8.73 mmol), 1,2,3,4-tetrahydroquinoline (1.33 g, 10 mmol, inisopropyl alcohol (50 ml) was heated at reflux for 6 hours. The solutionwas cooled and the solvent was removed on a rotary evaporator. The crudesolid was purified by flash chromatography over a silica gel column(SiO₂, 40 g, eluted with methylene chloride DCM, and 1-3% MeOH in DCM).The product thus purified weighed 2.0 g. This material was dissolved inethanol and was treated with a solution of fumaric acid (567 mg, 1.0 eq)in ethanol. The solids collected were recrystallized again from ethanol(50 ml) to yield 1.0 g of white crystals, as a hemifumarate, m.p.170-171° C.

ANALYSIS: Calculated for C₂₄ H₂₈ FN₃ O₂.0.5.C₄ H₄ O₄ : 66.79% C 6.47% H8.99% N; Found: 66.27% C 6.54% H 8.86% N

EXAMPLE 267N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetyl]-10,11-dihydro-5H-dibenz[b,f]azepinefumarate

A stirred mixture of 2-chloroacetyl-10,11-dihydro-5H-dibenz[b,f]azepine(6.6 g, 24.3 mmol), 4-(6fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g,22.7 mmol) and K₂ CO₃ (3.5 g, 40 mmol) in acetonitrile (300 ml) washeated at reflux for 4 hours. The insolubles were filtered, and thesolvent was removed on a rotary evaporator. The crude product waspurified by flash chromatography over a silica gel column (100 g of SiO₂; eluted with dichloromethane (DCM) and 1-2% CH₃ OH in DCM). The productthus obtained weighed 8.7 g as a yellow oil. A sample (1.5 g) of thismaterial was dissolved in ethanol and was treated with a solution offumaric acid in ethanol (360 mg/3 ml). The solids collected wererecrystallized from acetonitrile to yield 890 mg of white crystals, m.p.182-183° C.

ANALYSIS: Calculated for C₂₈ H₂₆ FN₃ O₂.C₄ H₄ O₄ : 67.24% C 5.29% H7.35% N; Found: 66.66% C 5.17% H 7.33% N

EXAMPLE 268 N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2ethoxyphthalimide hemihydrate

A mixture of 3-(4piperidinyl)-6-fluorobenzisoxazole (3.42 g, 15 mmol),N-(2-bromoethoxy)-phthalimide (4.3 g, 16 mmol) and K₂ CO₃ (26 g, 18mmol) in acetonitrile (150 ml) was heated at reflux for 2 hours. Thesolids were removed and the solvent was evaporated. The residue waspurified over a flash chromatography column (packed with SiO₂, 60 g;eluted with dichloromethane (DCM) and 1% CH₃ OH in DCM). The pureproduct thus obtained, weighing 6.8 g was crystallized from DCM:ethanol.Recrystallization from ethanol and i-propyl ether yielded white crystals(2.4 g, m.p. 125-127° C.) as the hemihydrate.

ANALYSIS: Calculated for C₂₂ H₂₀ FN₃ O₄.0.5.H₂ O: 63.15% C 5.05% H10.04% N 2.15% H₂ O; Found: 63.20% C 5.16% H 9.80% N 2.32% H₂ O

EXAMPLE 2693-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propylaminehydrochloride hydrate

A stirred mixture of3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propylphthalimide(6.2 g, 14.6 mmol) and hydrazine hydrate (1.4 g, 28 mmol) in methanol(300 ml) was heated at reflux for 4 hours, then at 65° C. for 16 hours.The mixture was cooled and the solvent was stripped to dryness. Thewhite residue was stirred with H₂ O (40 ml) and acidified with HCl topH=3. The milky white solids were filtered with the aid of Celite. Thelight yellow solution was basified with 50% NaOH to pH=9, then extractedwith methylene chloride (DCM, 3×180 ml). The DCM solution was washedwith brine, dried and stripped to give an oil (2.93 g) which solidifiedslowly. A 1 gm sample of this solid was treated with a HCl/MeOH solutionto precipitate out a hydrochloride salt. This salt was recrystallizedfrom ethanol=H₂ O to yield 0.52 g of white crystals, m.p.=150-152° C.

ANALYSIS: Calculated for C₁₅ H₂₀ FN₃ O₂.HCl.H₂ O: 51.80% C 6.67% H12.08% N; Found: 51.74% C 6.32% H 12.05% N

EXAMPLE 270N-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-pyridinecarboxamidedihydrochloride hydrate

To a mixture of2-[4-(6-fluoro-1,2-benzisoxazol-3-y)-1-piperidinyl]ethylamine (1.17 g,4.34 mmol) and triethylamine (1.08 g, 10.8 mmol) in chloroform (30 ml)was added nicotinoyl chloride hydrochloride (0.96 g, 5.4 mmol) in oneportion. The mixture was stirred for 1 hour at room temperature. Thesolution was diluted with methylene chloride (DCM) and washed with brineand dried over anhydrous MgSO₄. The solution was concentrated and thecrude product was purified by flash chromatography over a silica gelcolumn (SiO₂, 25 g; eluted with DCM and 1-3% MeOH in DCM). The free basethus purified weighed 1.7 g. This product was treated with 1M.HCl inethanol and recrystallized twice from methanol:isiproply ether to yieldwhite crystals, 1.19 g, m.p. 243-245° C. as a dihydrochloride hydrate.

ANALYSIS: Calculated for C₂₀ H₂₁ FN₄ O₂.2HCl.H₂ O: 52.30% C 5.49% H12.20% N 3.92% H₂ O; Found: 52.34% C 5.39% H 12.11% N 3.68% H₂ O

EXAMPLE 271N-[2-[4-(6-Fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-3-phenyl-2-quinoxalinaminedihydrochloride

A mixture of 2-[4-[(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethylamine(4.3 g, 16.3 mmol) and 2-chloro-3-phenylquinoxaline (4.7 g, 19.5 mmol)was heated at 160° C. for 5 hours in an autoclave. After standing atambient temperature for 2 days, the residue was partitioned between CH₂Cl₂ and H₂ O. The CH₂ Cl₂ extract was washed with H₂ O, dried with MgSO₄and concentrated to yield 7.5 g of a brown solid. The solid was purifiedby preparative HPLC (Water's Associates Prep LC System 500, using 2silica gel columns and 4.5% MeOH-CH₂ Cl₂ as eluent). Concentration oflater fractions afforded 2.3 g of the desired product as a yellow foam.A 1.4 g sample was suspended in MeOH (30 ml) and Et₂ O-HCl (6.0 ml of a1.0 m Et₂ O-HCl solution) was added. Initially a yellow solution formedand about 20 minutes later a precipitate began to form. The suspensionwas stirred for 30 minutes longer and anhydrous Et₂ O (100 ml) wasadded. The resultant light yellow solid was collected to give 1.5 g. Theproduct was stirred in boiling CH₃ CN (100 ml) for 1.0 hour and aftercooling the solid was isolated by filtration to afford 1.2 g of a lightyellow solid, m.p. 244-246° C.

ANALYSIS: Calculated for C₂₇ H₂₆ FN₇.2HCl: 60.00% C 5.22% H 18.14% N;Found: 59.79% C 5.27% H 18.34% N

EXAMPLE 2721,2-bis-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethanedifumarate

To a stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine(2.2 g, 10 mmol) and K₂ CO₃ (1.47 g, 11 mmol) in acetonitrile (50 ml)was added 1,2-dibromoethane (1 g, 5.4 mmol) dropwise at roomtemperature. The mixture was stirred at room temperature for 16 hours.The reaction mixture was filtered and the solvent was removed on arotary evaporator. The crude solid was purified by flash chromatography(SiO₂, 30 g; eluted with methylene chloride, DCM, and MeOH in DCM). Theproduct thus purified, weighed 513 mg. This solid was treated withfumaric acid (270 mg, 2 eq) in ethanol. The crystals collected wererecrystallized from ethanol:H₂ O to yield 630 mg of white crystals,m.p.=246-247° C.

ANALYSIS: Calculated for C₂₆ H₂₈ F₂ N₄ O₂ : 58.45% C 5.19% H 8.02% N;Found: 58.36% C 5.22% H 7.92% N

EXAMPLE 2731,3-Bis-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxypropanedihydrochloride

A stirred mixture of1-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (1.19g, 4.3 mmol) and 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (0.95 g,4.3 mmol) in isopropyl alcohol (50 ml) was heated at reflux for 1 hour,then stirred at 65° C. for 16 hours. The solvent was removed on a rotaryevaporator. The solid residues were purified by flash chromatographyover a silica gel column (SiO₂, 35 g; eluted with methylene chloride,DCM, and CH₃ OH in DCM). The product thus obtained, weighed 2.55 g. Thismaterial was dissolved in ethanol and was treated with a solution of HCl(1M in ether). The salt collected weighed 2.35 g, m.p.>270° C. dec.

ANALYSIS: Calculated for C₂₇ H₃₀ F₂ N₄ O₃.2HCl: 56.95% C 5.66% H 9.84%N; Found: 56.55% C 5.68% H 9.51% N

EXAMPLE 2742-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-phenyl-1,3-indandione

A mixture of 4-(6fluoro-1,2-benzisoxazol-3-yl)piperidine (2.2 g, 10mmol), K₂ CO₃ (1.6 g, 11.6 mmol) and2-toluenesulfonyl-2-phenyl-1,3-indandione (4.2 g, 10 mmol) inacetonitrile (50 ml) was heated at reflux for 3 hours. The mixture wascooled and the insolubles were filtered. The solvent was removed on arotary evaporator. The residue was purified twice using a flashchromatography column (SiO₂, 45 g and 40 g; eluted with DCM). Theproduct thus purified was recrystallized from ethanol (30 ml) andisopropyl ether, yield: 2.8 g, m.p. 149-150° C.

ANALYSIS: Calculated for C₂₉ H₂₅ FN₂ O₃ : 74.34% C 5.38% H 5.98% N;Found: 74.24% C 5.50% H 5.87% N

EXAMPLE 2752-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetonitrile

A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50mmol), K₂ CO₃ (8.5 g, 61.6 mmol) and 2-chloroacetonitrile (5.5 g, 73mmol) in acetonitrile (250 ml) was heated at reflux for 24 hours. Theinsolubles were filtered off and rinsed with methylene chloride (DCM).During concentration of the solvents on the rotary evaporator, crystalsappeared. The crystals were collected and weighed 5.79 g. The product inthe mother liquor was further purified by flash chromatography over asilica gel column (SiO₂, 70 g; eluted with DCM, and 1% CH₃ OH in DCM).The second crop of product thus obtained weighed 5.2 g. The total yieldwas 10.9 g. The sample was recrystallized once more form ethanol, m.p.130-132° C.

ANALYSIS: Calculated for C₁₄ H₁₄ FN₃ O: 64.85% C 5.44% H 16.21% N;Found: 64.68% C 5.32% H 16.26% N

EXAMPLE 2763-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionitrile

A mixture of 4-(6fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50mmol), K₂ CO₃ (8.5 g, 74 mmol) and 3-bromopropionitrile (8.2 g, 1.2 eq)in acetonitrile (300 ml) was heated at reflux for 24 hours. The mixturewas cooled and the insolubles were filtered. The solvent was removed ona rotary evaporator and the crude product was purified by flashchromatography over a silica gel column (SiO₂, 120 g). The product thuspurified weighed 8.94 g. Recrystallization from ethanol yielded thenitrile as white crystals 4.3 g, m.p. 100-101° C.

ANALYSIS: Calculated for C₁₅ H₁₆ FN₃ O: 65.92% C 5.90% H 15.37% N;Found: 65.87% C 5.87% H 15.37% N

EXAMPLE 2771-Phenoxycarbonyl-3-(1-phenoxycarbonyl-4-piperidinyl)-1H-indazole

To a suspension of 3-(1-methyl-4-piperidinyl)-1H-indazole (5.0 g, 23.2mmol) in DCM (100 ml) was added potassium carbonate (8.0 g, 58.0 mmol)followed by the dropwise addition of phenyl chloroformate (6.9 ml, 51.0mmol) at room temperature. After stirring for five days, the reactionwas filtered through a pad of celite and the solids were washed withDCM. The combined filtrates were concentrated and the remaining solidwas purified via flash column chromatography (silica gel, 10%methanol/DCM) to give 6.7 g of the1-phenoxycarbonyl-3-(1-methyl-4-piperidinyl)-1H-indazole as thehydrochloride salt. The free amine of the latter compound was preparedin Na₂ CO₃ (sat.) and extracted into EtOAc. Concentration of the organiclayer afforded 4.7 g of the free amine which was used without furtherpurification.

To a solution of1-phenoxycarbonyl-3-(1-methyl-4-piperidinyl)-1H-indazole) (4.7 g, 14.0mmol) in DCM (100 ml) was added potassium carbonate (0.85 g, 6.2 mmol)followed by phenyl chloroformate (2.1 ml, 15.4 mmol) at roomtemperature, under nitrogen. After stirring for 2 days, the reactionmixture was filtered through a pad of celite and the solids were washedwith DCM. The remaining oil was purified via flash column chromatography(silica gel, DCM) to give another oil which solidified from EtOAc/pet.ether. The white solid (4.2 g) was collected via filtration and washedwith pet ether, m.p. 113-116° C.

ANALYSIS: Calculated for C₂₆ H₂₃ N₃ O₄ : 70.74% C 5.25% H 9.52% N;Found: 70.47% C 5.17% H 9.38% N

EXAMPLE 278 [4-(6-Fluoro1H-indazol-3-yl)-1-piperazinyl]acetonitrile

A mixture of 6-fluoro-3-(4-piperazinyl)-1H-indazole (6.0 g, 2.7 mmol),NaHCO₃ (2.5 g, 3.0 mmol) chloroacetonitrile (2.5 g, 3.3 mmol) and CH₃ CN(150 mol) was stirred at reflux under N₂ for 18 hours. The cooledreaction was poured into H₂ O and the aqueous solution was extractedwith EtOAc. The EtOAc extract was washed with H₂ O, washed with brine,dried with MgSO₄ and concentrated to yield 7.0 g of a tan solid. A 1.3 gsample was recrystallized from EtOAc to yield 0.65 g of a beige solid,m.p. 154-156° C.

ANALYSIS: Calculated for C₁₃ H₁₄ FN₅ : 60.22% C 5.44% H 27.01% N; Found:59.97% C 5.55% H 26.91% N

EXAMPLE 279 1-[4-(3-Chloropropoxy)-3-methoxyphenyl]-2-hydroxyethanone

A solution of 1-(4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 ,17.7 mmol), [bis(trifluoroacetoxy)iodo]benzene (15.6 g, 36.2 mmol), H₂ O(18 ml), CF₃ CO₂ H (2.8 ml) and CH₃ CN (90 ml) was refluxed for 3 hours.The CH₃ CN was removed under reduced pressure and the resulting yellowliquid was partitioned between H₂ O and CH₂ Cl₂. The biphasic mixturewas filtered, the organic phase collected, washed with saturated NaHCO₃solution and concentrated to afford 1.5 g of an amorphous brown solid.The solid was flash chromatographed on silica gel, eluting the columnwith 5% EtOAc/CH₂ Cl₂. Concentration of similar fractions afforded 0.7 gof the compound as a pale yellow solid, m.p. 99-101° C.

EXAMPLE 2801-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-3-methoxyphenyl]-2-hydroxyethanone

A mixture of 3-(4piperidinyl)-6-fluoro-1,2-benzisoxazole (1.3 g, 5.8mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-2-hydroxyethanone (1.5 g,5.8 mmol), NaHCO₃ (1.5 g) and 1-methyl-2-pyrrolidinone (50 ml) wasstirred under N₂ at 100° C. for 6 hours. The reaction was poured into H₂O, and the aqueous suspension was extracted with EtOAc. The extract waswashed (H₂ O), dried (MgSO₄) and concentrated to afford the product.

This invention thus provides a group of chemical compounds that arecapable of producing antipsychotic effects and may be capable ofaffecting negative symptoms of schizophrenia in a beneficial manner. Inaddition, many of the compounds may also have reduced tendencies toproduce extrapyramidal side effects in mammals.

We claim:
 1. A compound of the formula ##STR133## wherein, X is --O--,--S--, --NH--, or --N(R₂)--; R₂ is selected from the group consisting oflower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl,alkoxycarbonyl, and phenysulfonyl groups;aryl is as defined hereinafter;p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine,bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino; A is--C(═O)--, --C(═S)--, --C(═CH₂)--, --C(═O)CH₂ --, --CH₂ CH₂ --, --CR₂₆═N--, or --CR₂₅ R₂₆ --; R₂₅ is hydrogen, (C₁ -C₆)alkyl, hydroxy, or (C₁-C₈) alkanoyloxy; R₂₆ is hydrogen or (C₁ -C₆)alkyl; either one of B_(y)and B_(z) is CH or N and the other is CH; U is O or S; q is 1, 2, 3, or4; R₁ is --CR₂₄ R₂₇ --(CR₂₃ R₂₄)_(n) --CR₂₄ R₂₇ -- where n is 0, 1, 2,or 3; or--CHR₂₄ --CH═CH--CHR₂₄ --, --CHR₂₄ --C.tbd.C--CHR₂₄ --, --CHR₂₄--CH═CH--CR₂₃ R₂₄ --CHR₂₄ --, --CHR₂₄ --CR₂₃ R₂₄ --CH═CH--CHR₂₄ --,--CHR₂₄ --C.tbd.C--CR₂₃ R₂₄ --CHR₂₄ --, or --CHR₂₄ --CR₂₃ R₂₄--C.tbd.C--CHR₂₄ --, the --CH═CH-- bond being cis or trans; R₂₃ ishydrogen, (C₁ -C₁₈) linear alkyl, phenyl, hydroxy, (C₁ -C₁₈)alkoxy,aryloxy, aryl(C₁ -C₁₈)alkyloxy, (C₁ -C₁₈)alkanoyloxy, hydroxy(C₁-C₆)alkyl, (C₁ -C₁₈)alkoxy(C₁ -C₆)alkyl, phenyl(C₁ -C₆)alkoxy, aryl(C₁-C₁₈)alkyloxy(C₁ -C₆)alkyl or (C₁ -C₁₈)alkanoyloxy(C₁ -C₆)alkyl, or##STR134## where Z₁ is lower alkyl, --OH, lower alkoxy, --CF₃, --NO₂,--NH₂, or halogen, and p is as previously defined, and wherein aryl isas defined hereinafter; and R₂₄ is hydrogen, (C₁ -C₁₈) linear alkyl,phenyl, hydroxy(C₁ -C₆)alkyl, (C₁ -C₁₈)alkoxy(C₁ -C₆)alkyl, phenyl(C₁-C₆)alkyloxy, aryl(C₁ -C₁₈)alkyloxy(C₁ -C₆)alkyl, (C₁-C₁₈)alkanoyloxy(C₁ -C₆)alkyl, or ##STR135## where Z₁ is as previouslydefined, and p is as previously defined, wherein aryl is as definedhereinafter; R₂₇ is hydrogen or R₂₄ and R₂₇ taken together with thecarbon to which they are attached form C═O or C═S; with the proviso thatR₂₃ is not hydrogen, (C₁ -C₁₈)linear alkyl, phenyl, or ##STR136## whenR₂₇ is hydrogen and R₂₄ is hydrogen, (C₁ -C₁₈)linear alkyl, phenyl, or##STR137## with the proviso that R₂₄ is not hydrogen, (C₁ -C₁₈)linearalkyl, phenyl, or ##STR138## when R₂₇ is hydrogen and n is 0; or whenR₂₇ is hydrogen and R₂₃ is hydrogen, (C₁ -C₁₈)linear alkyl, phenyl, or##STR139## or when R₁ is --CHR₂₄ --CH═CH--CHR₂₄ -- or --CHR₂₄--C.tbd.C--CHR₂₄ --; R₄ is hydrogen, lower alkyl, lower alkoxy, hydroxy,tri(C₁ -C₆)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl,amino, mono- or dialkylamino, (C₁ -C₁₈)acyl amino, (C₁ -C₁₈)alkanoyl,trifluoromethyl, chlorine, fluorine, bromine, nitro, --O--C(═O)--(C₁-C₁₈ straight or branched chain)alkyl or --C(═O)-aryl, wherein aryl isas defined hereinafter; in which aryl is phenyl or ##STR140## wherein R₅is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine,bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano,trifluoromethyl, or trifluoromethoxy; and, any hydroxyl group attachedto an aliphatic or aromatic carbon atom, or any primary or secondarynitrogen atom may be acylated with a (C₁ -C₁₈)alkanoyl group, inaddition, any nitrogen atom may alternatively be acylated with a (C₄-C₁₈)alkoxycarbonyl group; with the proviso that R₄ is not hydrogen whenY is 6-F, X is --O--, and n is 2, 3, or 4;all geometric, optical, andstereoisomers thereof; or a pharmaceutically acceptable acid additionsalt thereof.
 2. A compound of the formula ##STR141## wherein, X is--O--, --S--, --NH--, or --N(R₂)--; R₂ is selected from the groupconsisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl,alkanoyl, alkoxycarbonyl, and phenysulfonyl;aryl is as definedhereinafter; p is 2; Y is lower alkyl, hydroxy, chlorine, fluorine,bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino when Xis --S--, --NH--, or --N(R₂)--; Y is lower alkyl, trifluoromethyl,nitro, or amino when X is --O--; A is --C(═O)--, --C(═S)--, --C(═CH₂)--,--C(═O)CH₂ --, --CH₂ CH₂ --, --CR₂₆ ═N--, or --CR₂₅ R₂₆ --; R₂₅ ishydrogen, (C₁ -C₆)alkyl, hydroxy, or (C₁ -C₈) alkanoyloxy; R₂₆ ishydrogen or (C₁ -C₆)alkyl; either one of B_(y) and B_(z) is CH or N andthe other is CH; U is O or S; q is 1, 2, 3, or 4; R₁ is --CR₂₄ R₂₇--(CR₂₃ R₂₄)_(n) --CR₂₄ R₂₇ -- where n is 0, 1, 2, or 3; or--CHR₂₄--CH═CH--CHR₂₄ --, --CHR₂₄ --C.tbd.C--CHR₂₄ --, --CHR₂₄ --CH═CH--CR₂₃R₂₄ --CHR₂₄ --, --CHR₂₄ --CR₂₃ R₂₄ --CH═CH--CHR₂₄ --, --CHR₂₄--C.tbd.C--CR₂₃ R₂₄ --CHR₂₄ --, or --CHR₂₄ --CR₂₃ R₂₄ --C.tbd.C--CHR₂₄--, the --CH═CH-- bond being cis or trans; R₂₃ is hydrogen, (C₁ -C₁₈)linear alkyl, phenyl, hydroxy, (C₁ -C₁₈)alkoxy, aryloxy, aryl(C₁-C₁₈)alkyloxy, (C₁ -C₁₈)alkanoyloxy, hydroxy(C₁ -C₆)alkyl, (C₁-C₁₈)alkoxy(C₁ -C₆)alkyl, phenyl(C₁ -C₆)alkoxy, aryl(C₁ -C₁₈)alkyloxy(C₁-C₆)alkyl or (C₁ -C₁₈)alkanoyloxy(C₁ -C₆)alkyl, or ##STR142## where Z₁is lower alkyl, --OH, lower alkoxy, --CF₃, --NO₂, NH₂, or halogen, and pis as previously defined, and wherein aryl is as defined hereinafter;and R₂₄ is hydrogen, (C₁ -C₁₈) linear alkyl, phenyl, hydroxy(C₁-C₆)alkyl, (C₁ -C₁₈)alkoxy(C₁ -C₆)alkyl, phenyl(C₁ -C.sub.₆)alkyloxy,aryl(C₁ -C₁₈)alkyloxy(C₁ -C₆)alkyl, (C₁ -C₁₈)alkanoyloxy(C₁ -C₆)alkyl,or ##STR143## where Z₁ is as previously defined, and p is as previouslydefined, and wherein aryl is as defined hereinafter; R₂₇ is hydrogen orR₂₄ and R₂₇ taken together with the carbon to which they are attachedform C═O or C═S; R₄ is hydrogen, lower alkyl, lower alkoxy, hydroxy,tri(C₁ -C₆)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl,amino, mono- or dialkylamino, (C₁ -C₁₈)acyl amino, (C₁ -C₁₈)alkanoyl,trifluoromethyl, chlorine, fluorine, bromine, nitro, --O--C(═O)--(C₁-C₁₈ straight or branched chain)alkyl or --C(═O)-aryl, wherein aryl isas defined hereinafter; in which aryl is phenyl or ##STR144## wherein R₅is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine,bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano,trifluoromethyl, or trifluoromethoxy; and, any hydroxyl group attachedto an aliphatic or aromatic carbon atom, or any primary or secondarynitrogen atom may be acylated with a (C₄ -C₁₈)alkanoyl group, inaddition, any nitrogen atom may alternatively be acylated with a (C₄-C₁₈)alkoxycarbonyl group; with the proviso that R₄ is not hydrogen whenY is 6-F, X is --O--, and n is 2, 3, or 4;all geometric, optical, andstereoisomers thereof; or a pharmaceutically acceptable acid additionsalt thereof.
 3. A compound of the formula ##STR145## wherein, X is--O--, --S--, --NH--, or --N(R₂)--; R₂ is selected from the groupconsisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl,alkanoyl, alkoxycarbonyl, and phenysulfonyl groups;aryl is as definedhereinafter; p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine,fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, oramino; A is --C(═O), --C(═S)--, --C(═CH₂)--, --C(═O)CH₂ --, --CH₂ CH₂--, --CR₂₆ ═N--, or --CR₂₅ R₂₆ --; R₂₅ is hydrogen, (C₁ -C₆)alkyl,hydroxy, or (C₁ -C₈)alkanoyloxy; R₂₆ is hydrogen or (C₁ -C₆)alkyl;either one of B_(y) and B_(z) is CH or N and the other is CH; U is O orS; q is 1, 2, 3, or 4; R₁ is --CR₂₄ R₂₇ --(CR₂₃ R₂₄)_(n) --CR₂₄ R₂₇ --where n is 0, 1, 2, or 3; or--CHR₂₄ --CH═CH--CHR₂₄ --, --CHR₂₄--C.tbd.C--CHR₂₄ --, --CHR₂₄ --CH═CH--CR₂₃ R₂₄ --CHR₂₄ --, --CHR₂₄--CR₂₃ R₂₄ --CH═CH--CHR₂₄ --, --CHR₂₄ --C.tbd.C--CR₂₃ R₂₄ --CHR₂₄ --, or--CHR₂₄ --CR₂₃ R₂₄ --C.tbd.C--CHR₂₄ --, the --CH═CH-- bond being cis ortrans; R₂₃ is hydrogen, (C₁ -C₁₈) linear alkyl, phenyl, hydroxy, (C₁-C₁₈)alkoxy, aryloxy, aryl(C₁ -C₁₈)alkyloxy, (C₁ -C₁₈)alkanoyloxy,hydroxy(C₁ -C₆)alkyl, (C₁ -C₁₈)alkoxy(C₁ -C₆)alkyl, [phenyl(C₁-C₆)alkoxy,] aryl(C₁ -C₁₈)alkyloxy(C₁ -C₆)alkyl or (C₁-C₁₈)alkanoyloxy(C₁ -C₆)alkyl, or ##STR146## where Z₁ is lower alkyl,--OH, lower alkoxy, --CF₃, --NO₂, --NH₂, or halogen, and p is aspreviously defined, and wherein aryl is as defined hereinafter; and R₂₄is hydrogen, (C₁ -C₁₈) linear alkyl, phenyl, hydroxy(C₁ -C₆)alkyl, (C₁-C₁₈)alkoxy(C₁ -C₆)alkyl, phenyl(C₁ -C₆)alkyloxy, aryl(C₁-C₁₈)alkyloxy(C₁ -C₆)alkyl, (C₁ -C₁₈)alkanoyloxy(C₁ -C₆)alkyl, or##STR147## where Z₁ is as previously defined, and p is as previouslydefined, and wherein aryl is as defined hereinafter; R₂₇ is hydrogen orR₂₄ and R₂₇ taken together with the carbon to which they are attachedform C═O or C═S; R₄ is hydrogen, lower alkyl, lower alkoxy, hydroxy,tri(C₁ -C₆)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl,amino, mono- or dialkylamino, (C₁ -C₁₈)acyl amino, (C₁ -C₁₈)alkanoyl,trifluoromethyl, chlorine, fluorine, bromine, nitro, --O--C(═O)--(C₁-C₁₈ straight or branched chain)alkyl or --C(═O)-aryl; in which aryl isphenyl or ##STR148## wherein R₅ is hydrogen, lower alkyl, lower alkoxy,hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino,lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;and, any hydroxyl group attached to an aliphatic or aromatic carbonatom, or any primary or secondary nitrogen atom may be acylated with a(C₄ -C₁₈)alkanoyl group, in addition, any nitrogen atom mayalternatively be acylated with a (C₄ -C₁₈)alkoxycarbonyl group; with theproviso that R₄ is not hydrogen when Y is 6-F, X is --O--, and n is 2,3, or 4; with the proviso that when A is --C(═O), R₂₃ is not hydrogen,(C₁ -C₁₈)linear alkyl, phenyl, or ##STR149## when R₂₇ is hydrogen andR₂₄ is hydrogen, (C₁ -C₁₈)linear alkyl, phenyl, or ##STR150## with theproviso that when A is --C(═O), R₂₄ is not hydrogen, (C₁ -C₁₈)linearalkyl, phenyl, or ##STR151## when R₂₇ is hydrogen and n is 0; or whenR₂₇ is hydrogen and R₂₃ is hydrogen, (C₁ -C₁₈)linear alkyl, phenyl, or##STR152## or when R₁ is --CHR₂₄ --CH═CH--CHR₂₄ -- or --CHR₂₄--C.tbd.C--CHR₂₄ --; with the proviso that when A is --CH₂ CH₂ --, orwhen A is --CR₂₅ R₂₆ and R₂₅ and R₂₆ are both hydrogen or (C₁ -C₆)alkyl,then B_(y) and B_(z) are not both CH, unless X is --NR₂ and R₂ is notalkyl, or unless R₁ is subject to the proviso that R₂₃ is not hydrogenor (C₁ -C₁₈)linear alkyl when R₂₇ is hydrogen and R₂₄ is hydrogen or (C₁-C₁₈)linear alkyl, and the proviso that R₂₄ is not hydrogen or (C₁-C₁₈)linear alkyl when R₂₇ is hydrogen and n is 0, or when R₂₇ ishydrogen and R₂₃ is hydrogen or (C₁ -C₁₈)linear alkyl, or when R₁ is--CHR₂₄ --CH═CH--CHR₂₄ -- or --CHR₂₄ --C.tbd.C--CHR₂₄ --; with theproviso that A is not --CR₂₆ ═N-- when B_(y) and B_(z) are both CH;allgeometric, optical, and stereoisomers thereof; or a pharmaceuticallyacceptable acid addition salt thereof.
 4. A compound of the formula##STR153## wherein, X is --O--, --S--, --NH--, or --N(R₂)--; R₂ isselected from the group consisting of lower alkyl, aryl lower alkyl,aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl, and phenysulfonylgroups;aryl is as defined hereinafter; p is 1 or 2; Y is hydrogen, loweralkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy,trifluoromethyl, nitro, or amino; A is --C(═O)--, --C(═S)--,--C(═CH₂)--, --C(═O)CH₂ --, --CH₂ CH₂ --, --CR₂₆ ═N--, or --CR₂₅ R₂₆ --;R₂₅ is hydrogen, (C₁ -C₆)alkyl, hydroxy, or (C₁ -C₈) alkanoyloxy; R₂₆ ishydrogen or (C₁ -C₆)alkyl; either one of B_(y) and B_(z) is N and theother is CH; U is O or S; q is 1, 2, 3, or 4; R₁ is --CR₂₄ R₂₇ --(CR₂₃R₂₄)_(n) --CR₂₄ R₂₇ -- where n is 0, 1, 2, or 3; or--CHR₂₄--CH═CH--CHR₂₄ --, --CHR₂₄ --C.tbd.C--CHR₂₄ --, --CHR₂₄ --CH═CH--CR₂₃R₂₄ --CHR₂₄ --, --CHR₂₄ --CR₂₃ R₂₄ --CH═CH--CHR₂₄ --, --CHR₂₄--C.tbd.C--CR₂₃ R₂₄ --CHR₂₄ --, or --CHR₂₄ --CR₂₃ R₂₄ --C.tbd.C--CHR₂₄--, the --CH═CH-- bond being cis or trans; R₂₃ is hydrogen, (C₁ -C₁₈)linear alkyl, phenyl, hydroxy, (C₁ -C₁₈)alkoxy, aryloxy, aryl(C₁-C₁₈)alkyloxy, (C₁ -C₁₈)alkanoyloxy, hydroxy(C₁ -C₆)alkyl, (C₁-C₁₈)alkoxy(C₁ -C₆)alkyl, aryl(C₁ -C₁₈)alkyloxy(C₁ -C₆)alkyl or (C₁-C₁₈)alkanoyloxy(C₁ -C₆)alkyl, or ##STR154## where Z₁ is lower alkyl,--OH, lower alkoxy, --CF₃, --NO₂, --NH₂, or halogen, and p is aspreviously defined, and wherein aryl is as defined hereinafter; and R₂₄is hydrogen, (C₁ -C₁₈) linear alkyl, phenyl, hydroxy(C₁ -C₆)alkyl, (C₁-C₁₈)alkoxy(C₁ -C₆)alkyl, phenyl(C₁ -C₆)alkyloxy, aryl(C₁-C₁₈)alkyloxy(C₁ -C₆)alkyl, (C₁ -C₁₈)alkanoyloxy(C₁ -C₆)alkyl, or##STR155## where Z₁ is as previously defined, and p is as previouslydefined, and wherein aryl is as defined hereinafter; R₂₇ is hydrogen orR₂₄ and R₂₇ taken together with the carbon to which they are attachedform C═O or C═S; R₄ is hydrogen, lower alkyl, lower alkoxy, hydroxy,tri(C₁ -C₆)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl,amino, mono- or dialkylamino, (C₁ -C₁₈)acyl amino, (C₁ -C₁₈)alkanoyl,trifluoromethyl, chlorine, fluorine, bromine, nitro, --O--C(═O)--(C₁-C₁₈ straight or branched chain)alkyl or --C(═O)-aryl; in which aryl isphenyl or ##STR156## wherein R₅ is hydrogen, lower alkyl, lower alkoxy,hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino,lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;and, any hydroxyl group attached to an aliphatic or aromatic carbonatom, or any primary or secondary nitrogen atom may be acylated with a(C₄ -C₁₈)alkanoyl group, in addition, any nitrogen atom mayalternatively be acylated with a (C₄ -C₁₈)alkoxycarbonyl group; with theproviso that R₄ is not hydrogen when Y is 6-F, X is --O--, and n is 2,3, or 4; with the proviso that U is O, then A is not C═O;all geometric,optical, and stereoisomers thereof; or a pharmaceutically acceptableacid addition salt thereof.
 5. The compound of any one of claims 1 or 3,wherein A is C═O, B_(y) and B_(z) are CH, and U is O.
 6. The compound ofclaim 5, wherein X is --O--.
 7. The compound of claim 5, wherein X is--S--.
 8. The compound of claim 5, wherein X is --NH--.
 9. The compoundof claim 6, which isN-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-hydroxy-1-propyl]phthalimideand its pharmaceutically acceptable acid addition salts.
 10. Thecompound of claim 6, which is1-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-3-phthalimido-2-propyldecanoate and its pharmaceutically acceptable acid addition salts. 11.The compound of claim 6, which isN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-(1-decanoyl)oxyphthalimideand its pharmaceutically acceptable acid addition salts.
 12. A depotpharmaceutical composition, which comprises a pharmaceuticallyacceptable carrier and a therapeutically effective amount of thecompound of claim
 10. 13. A depot pharmaceutical composition, whichcomprises a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of the compound of claim
 11. 14. A method for providinga long acting antipsychotic effect, which comprises injecting into amammal an amount of the composition claim 12 sufficient to produce along acting antipsychotic effect.
 15. A method for providing a longacting antipsychotic effect, which comprises injecting into a mammal anamount of the composition claim 13 sufficient to produce a long actingantipsychotic effect.
 16. The compound of any one of claims 1 or 3,wherein A is --CH(OH)--, B_(y) and B_(z) are CH, and U is O.
 17. Thecompound of claim 16, wherein X is --O--.
 18. The compound of claim 16,wherein X is --S--.
 19. The compound of claim 16, wherein X is --NH--.20. The compound of claim 17, which is2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3-hydroxy-1H-isoindol-1-oneand its pharmaceutically acceptable acid addition salts.
 21. Thecompound of claim 18, which is2-[2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3-hydroxy-1H-isoindol-1-oneand its pharmaceutically acceptable acid addition salts.
 22. Thecompound of any one of claims 1 or 3, wherein A is C(═S), B_(y) andB_(z) are CH, and U is O.
 23. The compound of claim 22, wherein X is--O--.
 24. The compound of claim 23, which isN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]thiaphthalimideand its pharmaceutically acceptable acid addition salts.
 25. Thecompound of any one of claims 1 or 3, wherein A is C(═S), B_(y) andB_(z) are CH,and U is S.
 26. The compound of claim 25, wherein X is--O--.
 27. The compound of claim 27, which isN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,3-bis-thiaphthalimideand its pharmaceutically acceptabele acid addition salts.
 28. Thecompound of any one of claims 1 or 3, wherein A is C(CH₃)OH, B_(y) andB_(z) are CH, and U is O.
 29. The compound of claim 28, wherein X is--O--.
 30. The compound of claim 29, which is2,3-dihydro-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidyinyl]ethyl]-3-hydroxy-3-methyl-1-H-isoindol-1-oneand its pharmaceutically acceptable acid addition salts.
 31. Thecompound of any one of claims 1 or 3, wherein A is CH(CH₃), B_(y) andB_(z) are CH, and U is O.
 32. The compound of any one of claims 1 or 3,wherein A is C═CH₂, B_(y) and B_(z) are CH, and U is O.
 33. The compoundof claim 32, wherein X is --O--.
 34. The compound of claim 33, which is2,3-dihydro-2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-methylene-1H-isoindol-1-oneand its pharmaceutically acceptable acid addition salts.
 35. Thecompound of any one of claims 1 or 3, wherein A is CH₂, B_(y) and B_(z)are CH, and U is O.
 36. The compound of any one of claims 1 or 3,wherein A is --C(═O)CH₂ --, B_(y) and B_(z) are CH, and U is O.
 37. Thecompound of claim 36, wherein X is --O--.
 38. The compound of claim 37,which isN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-1,2,3,4-tetrahydroisoquinolin-1,3-dioneand its pharmaceutically acceptable acid addition salts.
 39. Thecompound of any one of claims 1 or 4, wherein A is C═O, B_(y) is CH,B_(z) is N, and U is O.
 40. The compound of any one of claims 1 or 3,wherein A is --CR₂₆ ═N--, B_(y) and B_(z) are CH, and U is O.
 41. Thecompound of any one of claims 1, 2, 3 or 4, wherein X is --NR₂ --. 42.An antipsychotic composition, which comprises the compound of any one ofclaims 2, 3 or 4 in an amount sufficient to produce an antipsychoticeffect, and a pharmaceutically acceptable carrier.
 43. A method oftreating psychoses, which comprises administering to a mammal apsychoses-treating amount of the compound of any one of claims 1-4. 44.An analgesic composition, which comprises the compound of any one ofclaims 1, 2, 3 or 4 in an amount sufficient to produce a pain-relievingeffect and a pharmaceutically acceptable carrier.
 45. A method ofalleviating pain, which comprises administering to a mammal apain-relieving effective amount of the compound of any one of claims 1,2, 3 or
 4. 46. A depot pharmaceutical composition, which comprises apharmaceutically acceptable carrier and a therapeutically effectiveamount of the compound of any one of claims 1, 2, 3 or 4, wherein thecompound contains an acylated hydroxy group, or an acylated amino group.47. The compound of claim 41, wherein R₂ is (C₁ -C₁₈)alkanoyl or (C₁-C₁₈)alkoxycarbonyl.
 48. The depot pharmaceutical composition of claim46, wherein the hydroxy group is acylated with a (C₄ -C₁₈)alkanoylgroup, or the amino group is acylated with a (C₄ -C₁₈)alkanoyl group ora (C₄ -C₁₈)alkoxycarbonyl group.
 49. The composition of claim 46, whichcontains a pharmaceutically acceptable oil.
 50. A method for providing along acting antipsychotic effect, which comprises injecting into amammal an amount of the composition of claim 46 sufficient to produce along acting antipsychotic effect.
 51. The composition of claim 49,wherein the oil is selected from the group consisting of coconut oil,peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, oliveoil, and esters of fatty acids and polyfunctional alcohols.
 52. Thecomposition of claim 48, which contains a pharmaceutically acceptableoil.
 53. A method for providing a long acting antipsychotic effect,which comprises injecting into a mammal an amount of the composition ofclaim 48 sufficient to produce a long acting antipsychotic effect. 54.The composition of claim 52, wherein the oil is selected from the groupconsisting of coconut oil, peanut oil, sesame oil, cottonseed oil, cornoil, soybean oil, olive oil, and esters of fatty acids andpolyfunctional alcohols.
 55. A method for providing a long actingantipsychotic effect, which comprises injecting into a mammal an amountof the composition of claim 54 sufficient to produce a long actingantipsychotic effect.
 56. A compound having the formula: ##STR157##wherein, X is --O--, --S--, ##STR158## R₂ is selected from the groupconsisting of lower alkyl, aryl lower alkyl, aryl, cycloalkyl, aroyl,alkanoyl, and phenylsulfonyl groups, wherein aryl is as definedhereinafter;p is 1 or 2; Y is hydrogen, lower alkyl, hydroxy, chlorine,fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, oramino, when p is 1; Y is lower alkoxy, hydroxy or halogen when p is 2and X is --O--; in which (R₁) is R₂₀, R₂₁ or R₂₂, wherein: R₂₀ is--(CH₂)_(n) --, where n is 2, 3, 4 or 5; R₂₁ is--CH₂ --CH═CH--CH₂ --,--CH₂ --C.tbd.C--CH₂ --, --CH₂ --CH═CH--CH₂ --CH₂, --CH₂ --CH₂--CH═CH--CH₂ --, --CH₂ --C.tbd.C--CH₂ --CH₂ --, or --CH₂ --CH₂--C.tbd.C--CH₂ --, the --CH═CH-- bond being cis or trans; R₂₂ is R₂₀ orR₂₁ in which one or more carbon atoms of R₂₀ or R₂₁ are substituted byat least one C₁ -C₆ linear alkyl group, phenyl group or ##STR159## whereZ₁ is lower alkyl, --OH, lower alkoxy, --CF₃, --NO₂, --NH₂ or halogen;R₄ is hydrogen, lower alkyl, lower alkoxy, hydroxy, amino, mono- ordialkylamino, C₁ -C₃ acyl amino, C₁ -C₆ alkanoyl, trifluoromethyl,chlorine, fluorine, bromine, ##STR160## (C₁ -C₁₂ straight or branchedchain) alkyl, or ##STR161## in which aryl is phenyl or ##STR162## whereR₅ is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine,bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano,trifluoromethyl, trifluoromethoxy; q is 1, 2, 3, or 4; with the provisothat R₄ is not hydrogen when Y is 6-F, X is --O--, and n is 2, 3, or4;all geometric, optical, and stereoisomers thereof, or apharmaceuticaly acceptable acid addition salt thereof.
 57. The compoundof claim 56, wherein X is --N(R₂)--.
 58. The compound of claim 56,wherein R₁ is --CH₂ --CH₂ --, --CH₂ CH₂ CH₂ --, --CH₂ CH(CH₃)--, or--CH(CH₃)CH₂ --.
 59. A pharmaceutical composition which comprises thecompound of claim 56 and a pharmaceutically acceptable carrier therefor.60. An antipsychotic composition, which comprises the compound of claim56 in an amount sufficient to produce an antipsychotic effect, and apharmaceutically acceptable carrier.
 61. A method of treating psychoses,which comprises administering to a mammal a psychoses-treating amount ofthe compound of claim
 56. 62. An analgesic composition, which comprisesthe compound of claim 56 in an amount sufficient to produce apain-relieving effect and a pharmaceutically acceptable carrier.
 63. Amethod of alleviating pain, which comprises administering to a mammal apain-relieving effective amount of the compound of claim
 56. 64. Thecompound of claim 57, wherein R₂ is (C₁ -C₁₂)alkanoyl.
 65. The compoundof claim 61, wherein X=0.
 66. The compound of claim 61, wherein X=S. 67.The compound of claim 61, wherein X=NH.
 68. The compound of claim 65,which isN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-fluorophthalimideand its pharmaceutically acceptable acid addition salts.
 69. Thecompound of claim 66, which isN-[2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]-4-methylphthalimideand its pharmaceutically acceptable acid addition salts.
 70. Thecompound of claim 66, which isN-[2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]phthalimideand its pharmaceutically acceptable acid addition salts.
 71. A depotpharmaceutical composition, which comprises a pharmaceuticallyacceptable carrier and a therapeutically effective amount of thecompound of claim
 68. 72. A method for providing a long actingantipsychotic effect, which comprises injecting into a mammal an amountof the composition claim 71 sufficient to produce a long actingantipsychotic effect.
 73. A method of treating psychoses, whichcomprises administering to a mammal a psychoses-treating amount of acompound of the formula ##STR163## wherein, X is --O--, --S--, --NH--,or --N(R₂)--; R₂ is selected from the group consisting of lower alkyl,aryl lower alkyl, aryl, cycloalkyl, aroyl, alkanoyl, alkoxycarbonyl, andphenysulfonyl groups;aryl is as defined hereinafter; p is 1 or 2; Y ishydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine,lower alkoxy, trifluoromethyl, nitro, or amino; A is --CR₂₆ ═N--; R₂₆ ishydrogen or (C₁ -C₆)alkyl; either one of B_(y) and B_(z) is CH or N andthe other is CH; U is O or S; q is 1, 2, 3, or 4; R₁ is --CR₂₄ R₂₇--(CR₂₃ R₂₄)_(n) --CR₂₄ R₂₇ -- where n is 0, 1, 2, or 3; or--CHR₂₄--CH═CH--CHR₂₄ --, --CHR₂₄ --C.tbd.C--CHR₂₄ --, --CHR₂₄ --CH═CH--CR₂₃R₂₄ --CHR₂₄ --, --CHR₂₄ --CR₂₃ R₂₄ --CH═CH--CHR₂₄ --, --CHR₂₄--C.tbd.C--CR₂₃ R₂₄ --CHR₂₄ --, or --CHR₂₄ --CR₂₃ R₂₄ --C.tbd.C--CHR₂₄--, the --CH═CH-- bond being cis or trans; R₂₃ is hydrogen, (C₁ -C₁₈)linear alkyl, phenyl, hydroxy, (C₁ -C₁₈)alkoxy, aryloxy, aryl(C₁-C₁₈)alkyloxy, (C₁ -C₁₈)alkanoyloxy, hydroxy(C₁ -C₆)alkyl, (C₁-C₁₈)alkoxy(C₁ -C₆)alkyl, aryl(C₁ -C₁₈)alkyloxy(C₁ -C₆)alkyl or (C₁-C₁₈)alkanoyloxy(C₁ -C₆)alkyl, or ##STR164## where Z₁ is lower alkyl,--OH, lower alkoxy, --CF₃, --NO₂, --NH₂, or halogen, and p is aspreviously defined, and wherein aryl is as defined hereinafter; and R₂₄is hydrogen, (C₁ -C₁₈) linear alkyl, phenyl, hydroxy(C₁ -C₆)alkyl, (C₁-C₁₈)alkoxy(C₁ -C₆)alkyl, phenyl(C₁ -C₆)alkyloxy, aryl(C₁-C₁₈)alkyloxy(C₁ -C₆)alkyl, (C₁ -C₁₈)alkanoyloxy(C₁ -C₆)alkyl, or##STR165## where Z₁ is as previously defined, and p is as previouslydefined, and wherein aryl is as defined hereinafter; R₂₇ is hydrogen orR₂₄ and R₂₇ taken together with the carbon to which they are attachedform C═O or C═S; R₄ is hydrogen, lower alkyl, lower alkoxy, hydroxy,tri(C₁ -C₆)alkylsilyloxy, hydroxy lower alkyl, alkanoyloxy lower alkyl,amino, mono- or dialkylamino, (C₁ -C₁₈)acyl amino, (C₁ -C₁₈)alkanoyl,trifluoromethyl, chlorine, fluorine, bromine, nitro, --O--C(═O)--(C₁-C₁₈ straight or branched chain)alkyl or --C(═O)-aryl; in which aryl isphenyl or ##STR166## wherein R₅ is hydrogen, lower alkyl, lower alkoxy,hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino,lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;and, any hydroxyl group attached to an aliphatic or aromatic carbonatom, or any primary or secondary nitrogen atom may be acylated with a(C₄ -C₁₈)alkanoyl group, in addition, any nitrogen atom mayalternatively be acylated with a (C₄ -C₁₈)alkoxycarbonyl group; with theproviso that R₄ is not hydrogen when Y is 6-F, X is --O--, and n is 2,3, or 4;all geometric, optical, and stereoisomers thereof; or apharmaceutically acceptable acid addition salt thereof.
 74. A depotpharmaceutical composition, which comprises a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundhaving the formula: ##STR167## wherein, X is --O--, --S--, ##STR168## R₂is selected from the group consisting of lower alkyl, aryl lower alkyl,aryl, cycloalkyl, aroyl, alkanoyl, and phenylsulfonyl groups, whereinaryl is as defined hereinafter;p is 1 or 2; Y is hydrogen, lower alkyl,hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy,trifluoromethyl, nitro, or amino, when p is 1; Y is lower alkoxy,hydroxy or halogen when p is 2 and X is --O--; in which (R₁) is R₂₀, R₂₁or R₂₂, wherein: R₂₀ is --(CH₂)_(n) --, where n is 2, 3, 4 or 5; R₂₁is--CH₂ --CH═CH--CH₂ --, --CH₂ --C.tbd.C--CH₂ --, --CH₂ --CH═CH--CH₂--CH₂ --, --CH₂ --CH₂ --CH═CH--CH₂ --, --CH₂ --C.tbd.C--CH₂ --CH₂ --, or--CH₂ --CH₂ --C.tbd.C--CH₂ --, the --CH═CH-- bond being cis or trans;R₂₂ is R₂₀ or R₂₁ in which one or more carbon atoms of R₂₀ or R₂₁ aresubstituted by at least one C₁ -C₆ linear alkyl group, phenyl group or##STR169## where Z₁ is lower alkyl, --OH, lower alkoxy, --CF₃, --NO₂,--NH₂ or halogen; R₄ is hydrogen, lower alkyl, lower alkoxy, hydroxy,amino, mono- or dialkylamino, C₁ -C₃ acyl amino, C₁ -C₆ alkanoyl,trifluoromethyl, chlorine, fluorine, bromine, ##STR170## (C₁ -C₁₂straight or branched chain)alkyl, or ##STR171## in which aryl is phenylor ##STR172## where R₅ is hydrogen, lower alkyl, lower alkoxy, hydroxy,chlorine, fluorine, bromine, iodine, lower monoalkylamino, lowerdialkylamino, nitro, cyano, trifluoromethyl, trifluoromethoxy; q is 1,2, 3, or 4; with the proviso that R₄ is not hydrogen when Y is 6-F, X is--O--, and n is 2, 3, or 4; and, any hydroxyl group attached to analiphatic or aromatic carbon atom, or any primary or secondary nitrogenatom may be acylated with a (C₄ ₁₄ C₁₈)alkanoyl group, in addition, anynitrogen atom may alternatively be acylated with a (C₄-C₁₈)alkoxycarbonyl group; all geometric, optical, and stereoisomersthereof, or a pharmaceutically acceptable acid addition saltthereof;wherein the compound contains an acylated hydroxy group, or anacylated amino group.
 75. The depot pharmaceutical composition of claim74, wherein the hydroxy group is acylated with a (C₄ -C₁₈)alkanoylgroup, or the amino group is acylated with a (C₄ -C₁₈)alkanoyl group ora (C₄ -C₁₈)alkoxycarbonyl group.
 76. The composition of claim 74, whichcontains a pharmaceutically acceptable oil.
 77. A method for providing along acting antipsychotic effect, which comprises injecting into amammal an amount of the composition of claim 74 sufficient to produce along acting antipsychotic effect.
 78. The composition of claim 76,wherein the oil is selected from the group consisting of coconut oil,peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, oliveoil, and esters of fatty acids and polyfunctional alcohols.
 79. Thecomposition of claim 75, which contains a pharmaceutically acceptableoil.
 80. A method for providing a long acting antipsychotic effect,which comprises injecting into a mammal an amount of the composition ofclaim 75 sufficient to produce a long acting antipsychotic effect. 81.The composition of claim 79, wherein the oil is selected from the groupconsisting of coconut oil, peanut oil, sesame oil, cottonseed oil, cornoil, soybean oil, olive oil, and esters of fatty acids andpolyfunctional alcohols.
 82. A method for providing a long actingantipsychotic effect, which comprises injecting into a mammal an amountof the composition of claim 81 sufficient to produce a long actingantipsychotic effect.
 83. The compound of claim 6, which isN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-4-(1-decanoyl)aminophthalimideand its pharmaceutically acceptable acid addition salts.
 84. A depotpharmaceutical composition, which comprises a pharmaceuticallyacceptable carrier and a therapeutically effective amount of thecompound of claim
 83. 85. A method for providing a long actingantipsychotic effect, which comprises injecting into a mammal an amountof the composition claim 84 sufficient to produce a long actingantipsychotic effect.
 86. The compound which is decanoic acid2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-ylester and its pharmaceutically acceptable acid addition salts.
 87. Adepot pharmaceutical composition, which comprises a pharmaceuticallyacceptable carrier and a therapeutically effective amount of thecompound of claim
 86. 88. A method for providing a long actingantipsychotic effect, which comprises injecting into a mammal an amountof the composition claim 87 sufficient to produce a long actingantipsychotic effect.
 89. A pharmaceutically acceptable acid additionsalt ofN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimide.90. The acid addition salt of claim 89, which isN-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimidehydrochloride.
 91. An antipsychotic composition, which comprises thecompound of claim 89 in an amount sufficient to produce an antipsychoticeffect, and a pharmaceutically acceptable carrier.
 92. A method oftreating psychoses, which comprises administering to a mammal apsychoses-treating amount of a compound of claim
 89. 93. Anantipsychotic composition, which comprises the compound of claim 90, inan amount sufficient to produce an antipsychotic effect, and apharmaceutically acceptable carrier.
 94. A method of treating psychoses,which comprises administering to a mammal a psychoses-treating amount ofthe compound of claim 90.